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Base excision repair

Base excision repair (BER) is a conserved DNA repair mechanism that identifies and corrects small, non-helix-distorting base lesions, such as those arising from oxidation, deamination, alkylation, and abasic sites, thereby preventing mutations and maintaining genomic integrity.^[1] Discovered in 1974 by Tomas Lindahl, BER targets damage that minimally affects DNA structure but can lead to base mispairing during replication, including oxidized bases like 8-oxoguanine, deaminated cytosine forming uracil, alkylated purines such as 3-methyladenine, and spontaneous abasic sites from glycosidic bond hydrolysis.^[2] The pathway is essential across all organisms, with defects linked to accelerated aging, neurodegeneration, inflammation, and various cancers, underscoring its role in cellular homeostasis and disease prevention.^[3] The BER process unfolds in a coordinated series of steps, beginning with damage-specific DNA glycosylases—such as OGG1 for oxidized guanines, UNG for uracils, and NEIL1/2 for additional oxidative lesions—that cleave the N-glycosylic bond to release the aberrant base, generating an abasic (AP) site.^[1] This site is then incised by AP endonuclease 1 (APE1), creating a single-strand break, followed by gap filling via DNA polymerase β (Pol β) in the predominant short-patch BER subpathway, which replaces one nucleotide, or through the long-patch subpathway involving 2–10 nucleotides with Pol β, PCNA, and FEN1.^[2] The repair is completed by DNA ligase III (with XRCC1 scaffold) or ligase I, sealing the nick to restore the DNA backbone.^[3] Specialized variants include transcription-coupled BER, which prioritizes oxidative lesions in actively transcribed genes using NEIL2 and Cockayne syndrome protein B (CSB), and replication-associated BER for S-phase damage.^[2] Beyond core repair, BER intersects with broader cellular processes, including immunoglobulin class-switch recombination in adaptive immunity via UNG2 and mitochondrial maintenance through nuclear-encoded enzymes like Pol β and ligase III.^[1] Dysregulation, such as in APE1 or PARP1 (a BER scaffold), heightens sensitivity to oxidative stress and chemotherapeutic agents, positioning BER components like PARP inhibitors as promising therapeutic targets in oncology.^[3] Single glycosylase deficiencies often yield mild phenotypes due to redundancy among the 11 mammalian enzymes, but disruptions in downstream factors like Pol β or XRCC1 cause severe viability issues in model organisms, highlighting BER's indispensable role in preventing endogenous DNA damage accumulation.^[2]

Overview of BER

Definition and Process

Base excision repair (BER) is a fundamental DNA repair pathway that addresses small, non-helix-distorting base lesions, such as those arising from oxidation, alkylation, and deamination, by excising the damaged nucleotide and replacing it with an undamaged one to maintain genomic integrity.^[2] This process is initiated upon recognition of a damaged base and proceeds through a coordinated series of enzymatic steps that remove the lesion without disrupting the overall DNA structure significantly.^[4] The BER mechanism unfolds in multiple steps: first, a DNA glycosylase recognizes and excises the damaged base by hydrolyzing the N-glycosidic bond, generating an apurinic/apyrimidinic (AP) site; second, an AP endonuclease incises the DNA backbone at the AP site, creating a single-strand break with a 3'-hydroxyl and 5'-deoxyribose phosphate terminus; finally, a DNA polymerase inserts one or more nucleotides to fill the gap, followed by ligation to seal the nick and restore the phosphodiester backbone.^[2] These steps ensure precise repair of the lesion while minimizing the risk of secondary damage.^[4] In contrast to nucleotide excision repair (NER), which targets bulky, helix-distorting adducts, or mismatch repair (MMR), which corrects replication errors, BER specifically handles non-bulky, base-specific damages that do not severely alter DNA conformation.^[2] BER is evolutionarily conserved across prokaryotes and eukaryotes, reflecting its essential role in genome stability, with human cells relying on it to process approximately 10,000 such repair events per day.00245-1)^[4]

Biological Importance

Base excision repair (BER) plays a pivotal role in safeguarding genomic integrity by repairing small, non-helix-distorting DNA lesions primarily caused by endogenous reactive oxygen species (ROS), such as those generated during cellular metabolism, as well as exogenous agents like ionizing radiation.^[5] These lesions, if unrepaired, can lead to base mispairing during DNA replication, resulting in point mutations that promote mutagenesis and increase cancer risk, while also threatening overall cell viability through cytotoxicity.^[6] By initiating the removal of damaged bases via DNA glycosylases and subsequent repair steps, BER prevents the accumulation of such mutations, thereby maintaining cellular homeostasis and reducing the propensity for oncogenic transformations.^[7] A key contribution of BER to genome stability lies in its capacity as the primary pathway for addressing oxidative DNA damage, which constitutes a major threat to DNA integrity. Defects in core BER components, such as the apurinic/apyrimidinic endonuclease or XRCC1, result in embryonic lethality in mouse models, underscoring the pathway's essentiality for early development and viability.^[8] In humans, BER processes an estimated 10,000–20,000 lesions per cell per day, predominantly from spontaneous hydrolytic and oxidative events, thereby averting the progressive buildup of genetic errors that could compromise organismal fitness.^[6] Beyond nuclear DNA maintenance, BER integrates with fundamental cellular processes to ensure seamless genome function. It supports DNA replication by clearing oxidative lesions that could stall replication forks, facilitates accurate transcription by removing damage that might block RNA polymerase progression, and is crucial for mitochondrial DNA (mtDNA) repair, where BER enzymes mitigate high levels of ROS-induced damage in this mutation-prone compartment.^[9] These multifaceted roles highlight BER's indispensable function in preserving both nuclear and mitochondrial genomic stability across diverse physiological contexts.^[10]

DNA Lesions Targeted by BER

Types of Base Damage

Base excision repair (BER) primarily addresses small, non-bulky DNA lesions that result in modified nucleobases or abasic sites, preserving genomic integrity by targeting damage that minimally disrupts the double helix structure. These lesions include various chemical modifications to DNA bases, such as oxidation, deamination, alkylation, and pyrimidine hydration. For instance, oxidation can produce 8-oxoguanine (8-oxoG), a mutagenic adduct that pairs with adenine instead of cytosine, leading to G-to-T transversions if unrepaired. Deamination events, like the conversion of cytosine to uracil, create mismatched bases that BER corrects to prevent C-to-T transitions. Alkylation modifications, exemplified by 3-methyladenine (3-meA), block DNA replication and transcription due to their inability to form proper Watson-Crick base pairs. Pyrimidine hydration products, such as thymine glycol, arise from oxidative damage to pyrimidines and similarly require BER intervention to avoid replication fork stalling.^[1]^[11] Abasic (AP) sites represent another critical class of damage repaired by BER, formed either through the action of DNA glycosylases that excise damaged bases or via spontaneous hydrolysis of the N-glycosidic bond. In mammalian cells, approximately 10,000 AP sites are generated daily, underscoring the pathway's essential role in handling this prevalent endogenous lesion. These sites lack a base but retain the phosphodeoxyribose backbone, creating a void in the DNA helix that, if unresolved, can lead to strand breaks or mutations during replication.^[1]^[11] A defining characteristic of BER-targeted lesions is their minimal distortion of the DNA helix, distinguishing them from bulky adducts repaired by nucleotide excision repair (NER), which cause significant helical bending or unwinding. This subtle structural perturbation allows BER enzymes to access and process the damage without requiring large-scale helix opening. DNA glycosylases initiating BER are classified as monofunctional or bifunctional based on their catalytic activities: monofunctional glycosylases hydrolyze only the N-glycosidic bond to release the damaged base, leaving an intact AP site, whereas bifunctional glycosylases perform both base removal and phosphodiester backbone incision via a beta-elimination or beta-delta-elimination mechanism, generating a single-strand break directly.^[1]^[11]

Sources and Consequences of Lesions

DNA lesions targeted by base excision repair (BER) arise from both endogenous and exogenous sources, with oxidative damage being particularly prevalent. Endogenous sources include reactive oxygen species (ROS) generated during normal cellular metabolism, such as mitochondrial respiration and enzymatic reactions, which oxidize DNA bases to form lesions like 8-oxoguanine (8-oxoG).^[12] Spontaneous hydrolysis of the glycosidic bond leads to abasic (AP) sites through depurination or depyrimidination, occurring at rates of approximately 5,000–10,000 events per mammalian cell per day.^[12] Replication errors can also contribute to base damage, such as spontaneous deamination of cytosine to uracil, which distorts base pairing and promotes mutations if unrepaired. Exogenous sources encompass environmental and genotoxic agents that induce similar base modifications. Ionizing radiation, including gamma rays and X-rays, generates ROS that cause oxidative base damage, such as 8-oxoG and thymine glycol.^[1] Alkylating agents, like those found in certain chemotherapeutic drugs or environmental pollutants (e.g., nitrosamines in tobacco smoke), add alkyl groups to DNA bases, forming N3-methyladenine or N7-methylguanine, which are BER substrates.^[1] Ultraviolet (UV) radiation, while primarily causing bulky lesions repaired by nucleotide excision repair, can indirectly generate ROS and oxidative base damage through photosensitization of cellular components.^[13] If left unrepaired, these lesions pose severe risks to genomic integrity and cellular function. Oxidative lesions like 8-oxoG are highly mutagenic, as 8-oxoG can mispair with adenine during replication, leading to G:C to T:A transversions.^[14] Unrepaired AP sites block DNA polymerases, resulting in single-strand breaks (SSBs) that can convert to double-strand breaks during replication, potentially causing cell cycle arrest, apoptosis, or oncogenic transformation.^[15] The prevalence of such damage underscores the need for efficient repair; for instance, oxidative lesions like 8-oxoG form at a rate of approximately 100–500 per human cell per day under normal physiological conditions.^[16] Accumulation of these lesions contributes to broader organismal impacts, including accelerated aging and increased cancer risk due to persistent mutational burden.

BER Pathways

Short-Patch Repair

Short-patch repair represents the predominant subpathway of base excision repair (BER), accounting for approximately 80% of all BER events and involving the replacement of a single nucleotide at the site of a damaged base.^[17] This pathway is particularly suited for repairing simple, non-bulky lesions such as uracil or 8-oxoguanine, which arise from oxidative or hydrolytic damage.^[1] The process begins after the initial recognition and removal of the damaged base by a DNA glycosylase, creating an apurinic/apyrimidinic (AP) site. AP endonuclease (APE1) then incises the DNA backbone 5' to the AP site, generating a 3'-hydroxyl end and a 5'-deoxyribose phosphate (5'-dRP) blocking group.^[1] DNA polymerase β (Pol β) subsequently performs dual functions: it inserts the correct nucleotide opposite the lesion using its polymerase activity and removes the 5'-dRP moiety via its β-lyase activity, creating a clean 1-nucleotide gap ready for ligation.^[1] Finally, the scaffold protein XRCC1 recruits DNA ligase III to seal the nick, completing the repair without the need for additional processing.^[1] A key feature of short-patch repair is the absence of flap formation, allowing direct ligation immediately after single-nucleotide insertion, which distinguishes it from more complex BER subpathways.^[1] This streamlined mechanism confers advantages such as rapidity and energy efficiency, making it ideal for addressing straightforward lesions in both replicating and quiescent cells.^[1] Moreover, short-patch repair operates effectively in both the nucleus and mitochondria, utilizing organelle-specific isoforms of the core proteins to maintain genomic integrity across cellular compartments.^[1]

Long-Patch Repair

Long-patch base excision repair (LP-BER) serves as an alternative pathway in base excision repair (BER), particularly for repairing clustered or oxidative DNA damage, where it synthesizes a patch of 2–10 nucleotides, displacing the downstream strand to form a flap structure that is subsequently removed.^[18] This mechanism is essential for handling complex lesions that cannot be resolved by single-nucleotide replacement, such as those arising from reactive oxygen species (ROS) that generate multiple proximate damages within one or two helical turns of DNA. In contrast to short-patch BER, which replaces only one nucleotide, LP-BER employs replicative machinery to ensure accurate restoration over longer stretches.^[18] The process begins with AP endonuclease (APE1) incising the DNA backbone 5' to the abasic site, generating a 3'-hydroxyl end and a 5'-deoxyribose phosphate (dRP) terminus.^[18] DNA synthesis is then initiated by DNA polymerase β (Pol β) inserting the first nucleotide, followed by extension via Pol β (in non-proliferating cells) or the replicative polymerases Pol δ or Pol ε in association with proliferating cell nuclear antigen (PCNA), resulting in strand displacement and flap formation.^[18] The flap endonuclease 1 (FEN1) cleaves the displaced oligonucleotide, and DNA ligase I (Lig I) seals the resulting nick to complete repair.^[18] LP-BER is triggered when short-patch repair fails, such as in cases of unrepaired 3'-phosphoglycolate blocks from oxidative strand breaks, which inhibit Pol β activity and ligation; these blocks are processed by APE1 or tyrosyl-DNA phosphodiesterase 1 (TDP1) to enable the extended synthesis.^[19] This pathway predominates in replicating cells, particularly during S-phase, where high levels of replication-associated proteins like PCNA and Pol δ/ε facilitate efficient processing.^[18] Poly(ADP-ribose) polymerase 1 (PARP1) contributes to signaling in LP-BER by binding nicked intermediates and regulating Pol β activity through autopoly(ADP-ribosyl)ation, which relieves inhibitory effects to promote synthesis.^[20]

Pathway Selection Mechanisms

The choice between short-patch and long-patch base excision repair (BER) pathways is influenced by the nature of the DNA lesion and the cellular context, ensuring efficient repair without excessive genomic instability. Short-patch BER, which replaces a single nucleotide, is typically selected for isolated or simple base lesions, while long-patch BER, involving 2-10 nucleotides, is favored for more complex damages such as clustered lesions or those resulting in blocked 3' ends. For instance, bifunctional DNA glycosylases like NEIL1 generate 3' blocking groups (e.g., 3' phosphate or oxidized sugar remnants) that hinder short-patch progression, thereby directing repair toward the long-patch pathway to displace and remove the obstructing moiety via strand displacement synthesis. Similarly, lesions like 2-deoxyribonolactone form stable DNA-protein crosslinks with DNA polymerase β during short-patch attempts, making long-patch BER the exclusive mechanism for their resolution.^[1] Protein scaffolds play a pivotal role in biasing pathway selection through specific interactions at the repair site. XRCC1 acts as a central scaffold for short-patch BER by recruiting DNA polymerase β and DNA ligase IIIα, facilitating rapid single-nucleotide gap filling and ligation, particularly under normal ATP conditions. In contrast, PARP1 and PCNA promote long-patch BER; PARP1 binds to the 5' deoxyribose phosphate intermediate and undergoes auto-PARylation to recruit PCNA, which in turn loads replicative polymerases δ or ε for multi-nucleotide synthesis and flap endonuclease 1 for flap removal. These scaffolds can compete, with XRCC1 inhibiting PCNA-dependent long-patch synthesis in some contexts, though XRCC1 may switch to support strand displacement under ATP depletion. Nucleosomal positioning further modulates this, as lesions within nucleosome cores restrict access to bulky long-patch machinery, favoring XRCC1-dependent short-patch repair.^[21]^[22]^[23] Cellular states and regulatory modifications fine-tune pathway selection to adapt to physiological demands. During replication stress or in S-phase, long-patch BER predominates due to the availability of replication-associated proteins like PCNA, which helps resolve oxidative lesions that could stall forks. In mitochondria, short-patch BER is preferentially utilized, relying on XRCC1-like coordination with polymerase γ and ligase III for single-nucleotide repair of mtDNA lesions, although long-patch capacity exists for more severe damages. Post-translational modifications, such as PARylation by PARP1, serve as key regulatory signals; auto-PARylation of PARP1 at BER intermediates promotes dissociation of short-patch factors and recruitment of long-patch components, thereby switching the pathway and enhancing repair of clustered or oxidative damages. Additional signals, like HMGB1 binding, further direct toward long-patch by facilitating strand displacement.^[1]^[24]^[25]

Core Proteins in BER

DNA Glycosylases

DNA glycosylases initiate base excision repair (BER) by specifically recognizing and excising damaged or inappropriate bases from the DNA strand. These enzymes hydrolyze the N-glycosidic bond linking the aberrant base to the deoxyribose sugar, thereby creating an apurinic/apyrimidinic (AP) site that serves as the substrate for subsequent repair steps.^[26] This process is essential for maintaining genomic integrity against a variety of endogenous and exogenous DNA lesions.^[5] Human cells express 11 distinct DNA glycosylases, each exhibiting high specificity for particular types of base damage or mismatches.^[27] They are broadly classified into monofunctional and bifunctional categories based on their enzymatic activities. Monofunctional glycosylases, such as uracil-DNA glycosylase (UNG), which removes uracil resulting from cytosine deamination, and 8-oxoguanine DNA glycosylase 1 (OGG1), which targets the oxidative lesion 8-oxoguanine, perform only the base excision step without further backbone cleavage.^[28] In contrast, bifunctional glycosylases, exemplified by endonuclease VIII-like 1 (NEIL1) and NEIL2, possess both glycosylase and intrinsic AP lyase activities; these enzymes excise damaged bases such as ring-opened purines or oxidized pyrimidines and subsequently cleave the DNA backbone via β-elimination at the resulting AP site.^[29] Other notable examples include methylpurine DNA glycosylase (MPG), which removes alkylated purines like 3-methyladenine, and thymine DNA glycosylase (TDG), which excises thymine from G/T mismatches arising from cytosine deamination.^[27] The mechanism of action for DNA glycosylases involves a conserved base-flipping strategy, where the enzyme slides along the DNA duplex, interrogates potential lesions, and extrudes the target base from the helical stack into a specialized active site pocket for precise verification and hydrolysis.^[28] This dynamic process, often accompanied by DNA bending to facilitate base eversion, enables the enzymes to achieve remarkable lesion specificity while minimizing off-target activity on normal bases.^[11] Structural studies of various glycosylases, including UNG and OGG1, have revealed conserved motifs such as the helix-hairpin-helix domain that stabilize the extrahelical base and position catalytic residues for N-glycosidic bond cleavage.^[28]

AP Endonucleases

AP endonucleases are essential enzymes in the base excision repair (BER) pathway that recognize apurinic/apyrimidinic (AP) sites—abasic lesions generated by DNA glycosylases—and incise the DNA phosphodiester backbone to initiate strand break repair.^[30] These enzymes process the sugar-phosphate backbone specifically at AP sites, creating a single-strand break that allows downstream repair factors to replace the damaged nucleotide. In humans, the primary AP endonuclease is apurinic/apyrimidinic endonuclease 1 (APE1), also known as APEX1 or REF-1, which accounts for more than 95% of the total cellular AP endonuclease activity.^[31] APE1 functions as a structure-specific endonuclease, hydrolyzing the phosphodiester bond 5' to the AP site in a magnesium ion (Mg²⁺)-dependent manner, thereby generating a 3'-hydroxyl (3'-OH) terminus and a 5'-deoxyribose phosphate (5'-dRP) end.^[30] This incision creates an optimal substrate for subsequent BER steps, such as DNA synthesis and ligation. The enzyme's active site coordinates two Mg²⁺ ions via aspartate residues D70, E96, and D308, positioning a nucleophilic water molecule—activated by D210 and N212—for attack on the scissile phosphate.^[30] Structurally, APE1 comprises a compact catalytic core (residues 43–318) with a positively charged DNA-binding surface that engages double-stranded DNA over a ~10 base pair footprint, bending the helix by ~20° and extruding the AP site into the active site for precise cleavage.^[30] This mechanism ensures high specificity for AP sites, with rapid incision rates (up to 500 s⁻¹) at solvent-exposed positions in chromatin.^[30] In addition to its endonuclease activity, APE1 exhibits 3'-phosphodiesterase activity, which removes certain 3'-blocking groups, such as 3'-phosphates, from DNA strand breaks to generate clean 3'-OH ends suitable for repair.^[32] This multifunctional capability enhances APE1's role in processing oxidative DNA damage during BER. While APE1 dominates AP site incision, a paralog, APE2, provides partial redundancy, particularly in proliferating cells where it contributes to end processing at certain lesions.^[33] However, APE1 is indispensable for cellular viability, as complete knockout of the APEX1 gene is embryonically lethal in mice, underscoring its non-redundant essential functions in DNA repair.^[33] Beyond repair, APE1 regulates transcription factors through redox modifications, but its primary impact in BER stems from efficient AP site processing to prevent mutagenesis from unrepaired abasic lesions.^[34]

End-Processing Enzymes

End-processing enzymes in base excision repair (BER) play a crucial role in preparing DNA strand break intermediates by removing blocking groups at the 3' and 5' termini, ensuring the generation of ligatable 3'-OH and 5'-phosphate ends for subsequent repair steps. These enzymes act after the initial incision at abasic sites or following β-elimination by bifunctional DNA glycosylases, which can leave incompatible termini such as 3'-phosphate or 5'-deoxyribosephosphate (dRP) groups. By resolving these blocks, end-processing enzymes prevent repair stalling and maintain genomic stability, particularly in response to oxidative damage or ionizing radiation-induced lesions.^[35] Polynucleotide kinase/phosphatase (PNKP) is a bifunctional enzyme central to end-processing in BER, possessing 3'-phosphatase activity to remove 3'-phosphate groups generated by the β,δ-elimination mechanism of bifunctional glycosylases like NEIL1 and NEIL2, which target oxidized bases such as thymine glycol or 8-oxoguanine. Its 5'-kinase activity phosphorylates 5'-hydroxyl ends to create 5'-phosphates, facilitating ligation in both short-patch and long-patch BER pathways. PNKP is particularly important in long-patch BER, where it ensures a clean 3'-OH primer for DNA polymerase extension beyond a single nucleotide. Defects in PNKP, such as mutations associated with microcephaly, seizures, and developmental delay syndrome, lead to hypersensitivity to oxidative stress agents like hydrogen peroxide, underscoring its essential role in repairing reactive oxygen species-induced damage.^[36]^[37]^[38] Tyrosyl-DNA phosphodiesterase 1 (TDP1) specifically resolves 3'-phosphotyrosyl adducts formed by stalled topoisomerase I complexes, which can arise during BER of oxidative lesions or as secondary damage from ionizing radiation. TDP1 hydrolyzes the phosphodiester bond linking the tyrosine residue to the 3'-DNA end, generating a 3'-phosphate that is further processed by PNKP's phosphatase activity. This enzyme's activity is vital for preventing persistent strand breaks that could escalate to double-strand breaks, and TDP1 deficiencies are linked to spinocerebellar ataxia with axonal neuropathy, highlighting its protective function against genotoxic stress. In certain contexts, the MRE11-Rad50-NBS1 complex contributes to end-processing by resecting 3'-blocked termini, including topoisomerase adducts, particularly in alternative BER pathways triggered by ionizing radiation or complex lesions.^[39]^[40]

DNA Polymerases

In base excision repair (BER), DNA polymerases are essential for filling the single-nucleotide gap generated after lesion removal and end processing in the short-patch pathway, or the multi-nucleotide gap in the long-patch pathway. The primary polymerase for short-patch BER is DNA polymerase β (Pol β), a member of the X family, which catalyzes the insertion of a single correct nucleotide opposite the template strand in a template-dependent manner.^[5] Pol β exhibits high fidelity, with a base substitution error rate of approximately 10^{-5} during gap filling, ensuring accurate repair while avoiding translesion synthesis across undamaged template regions.^[41] Additionally, Pol β possesses intrinsic 5'-deoxyribose phosphate (dRP) lyase activity, which cleaves the dRP residue at the 5' margin of the gap, generating a clean 5'-phosphate terminus for subsequent ligation.^[9] This dual polymerase and lyase functionality allows Pol β to efficiently process repair intermediates in a coordinated manner.^[42] Pol β interacts directly with the scaffold protein XRCC1, which enhances its recruitment to repair sites and stabilizes the repair complex, promoting efficient short-patch BER.^[43] This coordination ensures rapid gap filling and minimizes error-prone processing of oxidative or alkylative lesions.^[44] In the long-patch BER pathway, which replaces 2-10 nucleotides, replicative DNA polymerases δ (Pol δ) and ε (Pol ε), both B-family enzymes, perform strand-displacement synthesis. These polymerases are stimulated by the proliferating cell nuclear antigen (PCNA) clamp and replication factor C (RFC) loader, enabling processive multi-nucleotide insertion while displacing the downstream strand.^[45] In mitochondria, mitochondrial BER (mtBER) employs DNA polymerase γ (Pol γ), the sole replicative polymerase in this compartment, for gap filling in both short- and long-patch modes. Pol γ, also a B-family enzyme, is adapted for mitochondrial conditions and possesses dRP lyase activity to process 5'-dRP blocks, though it is less efficient than nuclear Pol β for single-nucleotide insertions.^[46] This specialization supports repair of oxidative damage prevalent in mitochondrial DNA.^[47]

Flap Endonuclease

Flap endonuclease 1 (FEN1) is a structure-specific endonuclease that plays a crucial role in long-patch base excision repair (BER) by processing the 5'-flap intermediate generated during strand displacement synthesis.^[48] In this pathway, FEN1 specifically recognizes and cleaves the displaced 5'-flap structure at the junction to generate a ligatable nick at the repair site. This precise incision ensures the removal of the flap without excessive degradation, maintaining genome integrity during the repair of base lesions. FEN1 operates through two primary modes: a 5'-3' exonuclease activity that progressively removes nucleotides from the flap end and an endonuclease mode that directly cleaves the flap junction.^[48] In long-patch BER, the endonuclease activity predominates on flap structures of 2-10 nucleotides, stimulated by proliferating cell nuclear antigen (PCNA), which enhances FEN1's efficiency through direct protein-protein interaction and recruitment to the repair site.^[49] This PCNA dependence coordinates FEN1 with the replicative DNA synthesis machinery, distinguishing its function in BER gap repair from its broader role in Okazaki fragment processing during replication.^[50] While FEN1 is the primary enzyme, alternative nucleases such as exonuclease 1 (EXO1) and GEN1 can provide backup flap processing in long-patch BER, albeit with reduced efficiency and specificity.^[50] These alternatives ensure pathway robustness but cannot fully compensate for FEN1 loss, highlighting its specialized, BER-specific contributions to flap resolution in post-synthesis repair intermediates.^[48] Defects in FEN1, including mutations like L209P in its nuclease domain, impair flap cleavage and lead to accumulation of unprocessed 5'-flaps, resulting in persistent DNA intermediates and replication stress.^[51] Such deficiencies cause genome instability, characterized by increased double-strand breaks, chromosomal aberrations, and aneuploidy, which promote cellular transformation.^[51] FEN1 mutations and haploinsufficiency are linked to cancer predisposition, as evidenced by accelerated tumor development in model systems and associations with colorectal and other malignancies.^[51]

DNA Ligase

In base excision repair (BER), DNA ligase catalyzes the final step of sealing nicks in the DNA backbone after lesion removal and gap filling, ensuring the restoration of genomic integrity. In the short-patch BER pathway, which replaces a single damaged nucleotide, DNA ligase III (LIG3), in complex with the scaffolding protein XRCC1, ligates the nick between the newly inserted nucleotide and the downstream DNA strand. This ATP-dependent process is highly efficient, with LIG3 recognizing and joining clean 3'-hydroxyl and 5'-phosphate termini left after deoxyribose phosphate removal. The LIG3-XRCC1 interaction stabilizes the complex and enhances ligation fidelity at single-nucleotide repair sites. In contrast, the long-patch BER pathway, involving the synthesis of 2–10 nucleotides to replace the damaged region, primarily utilizes DNA ligase I (LIG1) to seal the resulting multi-nucleotide gap. LIG1 interacts with proliferating cell nuclear antigen (PCNA), which facilitates its recruitment to the repair site during the strand displacement and flap processing steps, promoting efficient closure of larger patches. This PCNA-mediated association underscores LIG1's role in coordinating ligation with replicative-like synthesis in long-patch repair. The mechanistic action of both LIG1 and LIG3 in BER follows a conserved three-step process: first, the ligase enzyme undergoes adenylation by reacting with ATP to form a ligase-AMP intermediate; second, the AMP moiety is transferred to the 5'-phosphate end of the nick, creating a pyrophosphate linkage; and third, the 3'-hydroxyl group attacks the activated 5'-phosphoryl, forming a phosphodiester bond and releasing AMP. This ATP-dependent mechanism ensures precise joining without introducing errors, though its efficiency can be modulated by substrate geometry and accessory proteins. Beyond nuclear BER, LIG3 plays a critical role in mitochondrial base excision repair (mtBER), where it seals nicks in mitochondrial DNA to counteract oxidative damage. LIG3 is the sole ligase in mitochondria, and its deficiency leads to mtDNA depletion and cellular lethality, highlighting its indispensability. However, functional redundancy between LIG3 and LIG1 in nuclear BER provides robustness, as LIG1 can compensate for LIG3 loss, preventing overall repair failure and organismal viability issues.

Regulation and Interactions

Transcription-Coupled BER

Transcription-coupled base excision repair (TC-BER) is a specialized subpathway of BER that preferentially targets and repairs oxidative DNA base lesions on the transcribed strand of active genes, ensuring the integrity of actively transcribed genomic regions. This process is initiated when RNA polymerase II (Pol II) encounters a base lesion during transcription elongation, leading to polymerase stalling and recruitment of BER factors to the site. Unlike global genome BER, which operates uniformly across the genome, TC-BER is triggered specifically by transcription machinery, allowing for rapid resolution of lesions that could otherwise block gene expression.^[52] Central to TC-BER is the Cockayne syndrome group B protein (CSB, also known as ERCC6), which binds to stalled Pol II and facilitates the recruitment of core BER enzymes, including DNA glycosylases such as OGG1 and NEIL family members. CSB enhances the activity of these glycosylases at lesion sites within the transcription bubble, promoting efficient base excision and downstream repair steps like AP endonuclease cleavage and gap filling. This coordination forms a transient repair complex, often termed the "BERosome," which operates in close proximity to the transcription apparatus. Studies in CSB-deficient cells demonstrate significantly impaired repair of oxidative lesions in transcribed strands, underscoring CSB's pivotal role.^[52] TC-BER exhibits a bias toward oxidative damage, particularly in promoter regions and actively transcribed genes, where lesions like 8-oxoguanine (8-oxoG) and thymine glycol accumulate due to reactive oxygen species. Recent investigations highlight the NEIL glycosylases, especially NEIL2, as key initiators in TC-BER; NEIL2 preferentially excises oxidized pyrimidines from single-stranded DNA within the transcription bubble, with structural studies revealing enhanced substrate affinity in this context. In vitro reconstitution experiments confirm that NEIL2, in conjunction with Pol II and other BER factors, drives lesion removal on the transcribed template. Compared to global BER, TC-BER shows higher glycosylase recruitment efficiency in chromatin-associated transcribed regions, resulting in preferential repair rates on the transcribed strand—evident from faster clearance of 8-oxoG in active genes versus non-transcribed areas. These features distinguish TC-BER as a transcription-dependent mechanism optimized for maintaining transcriptional fidelity in mammalian cells.^[52]^[53]

Coordination with Other DNA Repair Pathways

Base excision repair (BER) integrates with nucleotide excision repair (NER) to address complex DNA lesions, where NER primarily excises bulky adducts, leaving behind residual base damage that BER subsequently processes through glycosylases like OGG1 and endonucleases such as APE1.^[54] This coordination is facilitated by shared proteins, notably XPG (also known as ERCC5), an endonuclease that functions in NER for dual incisions but also enhances BER efficiency by stabilizing repair intermediates and promoting the removal of oxidative lesions like 8-oxoguanine.^[54] Deficiencies in XPG, as observed in xeroderma pigmentosum complementation group G, impair this interplay and increase sensitivity to oxidative damage.^[54] Recent studies highlight BER's cooperation with double-strand break (DSB) repair pathways, particularly in post-mitotic tissues like the brain, where clustered oxidative lesions generate single-strand breaks (SSBs) that BER processes, potentially converting them into DSBs if unrepaired.^[55] A 2024 investigation in mouse models demonstrated that BER activity, which is 4- to 10-fold higher than other pathways like MMR and NER in glial cells and up to 10-fold elevated in neurons relative to glia for key BER proteins such as APE1, modulates DSB formation by handing off SSB intermediates to non-homologous end joining (NHEJ) via Ku70/Ku80 or homologous recombination (HR) via MRE11, preventing persistent breaks that accumulate with age (from 7 to 75 weeks).^[55] Antioxidant interventions reduced this SSB-to-DSB conversion by 30-50%, underscoring the protective role of this BER-DSB axis in maintaining genomic stability amid high oxidative stress.^[55] BER also overlaps with mismatch repair (MMR) in addressing oxidative mismatches, such as 8-oxoG paired with adenine, where BER glycosylases like MUTYH remove the erroneous base and MMR proteins (MSH2, MSH6, MLH1) recognize the distortion for excision.^[56] DNA polymerase β (Pol β), a core BER enzyme, aids MMR by filling gaps post-excision, as evidenced by synthetic lethality between POLB silencing and MSH2 deficiency, which elevates nuclear 8-oxoG levels.^[56] This functional redundancy ensures robust repair of oxidative damage, with combined deficiencies in BER and MMR components (e.g., Msh2−/−/Mutyh−/− mice) resulting in synergistic lesion accumulation.^[56] Single-molecule imaging studies from 2023 to 2025 have revealed dynamic handoffs in BER, where scaffold proteins like XRCC1, through its BRCT domain, orchestrate sequential enzyme recruitment and substrate channeling at damage sites.^[57] These techniques, including atomic force microscopy, show XRCC1 facilitating rapid transitions from Pol β gap-filling to ligase sealing, minimizing intermediate exposure and enhancing repair fidelity in real-time.^[57] Such insights emphasize XRCC1's role as a central coordinator, stabilizing nicked intermediates and preventing crosstalk errors with other pathways.^[57]

BER in Disease and Aging

Associations with Cancer

Deficiencies in base excision repair (BER) pathways significantly elevate mutation rates in cells, thereby promoting genomic instability and facilitating oncogenesis. Impaired BER fails to adequately remove oxidative and alkylative DNA lesions, leading to persistent damage that can result in transversion mutations during replication. For instance, variants of DNA polymerase β (Pol β), a key BER enzyme, have been identified in approximately 30% of analyzed human tumors, often co-existing with wild-type Pol β and contributing to error-prone repair that accelerates tumorigenesis.^[58] Overexpression of BER components, such as apurinic/apyrimidinic endonuclease 1 (APE1), is frequently observed in various cancers and correlates with enhanced resistance to chemotherapeutic agents like cisplatin. In non-small cell lung cancer, elevated APE1 levels are associated with poor prognosis and reduced sensitivity to platinum-based therapies, underscoring BER's role in tumor survival under genotoxic stress. Mouse models further support these associations; knockouts of BER glycosylases like OGG1 and MYH predispose animals to tumor development, particularly in the intestine and lung, due to accumulated oxidative lesions.^[59]^[60] A prominent example involves unrepaired 8-oxoguanine (8-oxoG), a BER-targeted oxidative lesion that, if not excised by OGG1, mispairs with adenine during replication, yielding G:C to T:A transversions. These mutations frequently occur in hotspots such as the KRAS oncogene, driving activation in colorectal and lung cancers. BER's function as a surveillance mechanism against chemical-induced DNA damage from environmental carcinogens includes revealing synthetic lethality opportunities; for example, inhibition of Pol β sensitizes BRCA1/2-deficient tumors to PARP inhibitors by exacerbating unrepaired single-strand breaks.^[61]^[62]

Epigenetic Deficiencies in Cancer

Base excision repair (BER) plays a critical role in maintaining epigenetic integrity by repairing modified bases that arise during DNA demethylation processes. Deficiencies in BER components involved in epigenetic maintenance, such as methyl-CpG-binding domain protein 4 (MBD4) and Nei endonuclease VIII-like 1 (NEIL1), are frequently observed in cancers and contribute to aberrant DNA methylation patterns that promote tumorigenesis.^[63]^[64] MBD4 functions as a methyl-CpG-specific thymine glycosylase in BER, recognizing and excising thymine from G:T mismatches resulting from deamination of 5-methylcytosine (5mC) at CpG sites. In colorectal cancers, particularly those with microsatellite instability due to mismatch repair deficiency, inactivating mutations in MBD4 occur in 20-45% of cases, leading to increased C-to-T transition mutations at CpG islands.^[65]^[66] These mutations impair the repair of deaminated 5mC, resulting in hypermutation at methylated CpG hotspots and accelerated tumor progression, as evidenced by enhanced gastrointestinal tumor formation in Mbd4-deficient mouse models combined with Apc mutations.^[67]^[68] NEIL1 acts as a DNA glycosylase in BER that removes oxidatively damaged pyrimidines, including 5-hydroxycytosine (5-OHC), to prevent mutagenic lesions. Downregulation of NEIL1 is common in lung adenocarcinoma and invasive breast cancers, where it correlates with poor patient survival and increased somatic mutation loads.^[64]^[69] This downregulation often results from promoter hypermethylation of the NEIL1 gene itself, leading to persistence of unrepaired oxidative lesions like 5-OHC, which can disrupt local epigenetic marks and contribute to genome-wide hypermethylation patterns observed in these tumors.^[70] BER errors, particularly those involving thymine DNA glycosylase (TDG), disrupt active demethylation of 5mC by failing to excise oxidation intermediates such as 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which are generated by ten-eleven translocation (TET) enzymes.^[71]^[72] Impaired TDG-BER activity leads to accumulation of these intermediates or incomplete demethylation cycles, promoting hypermethylation and aberrant transcriptional silencing of tumor suppressor genes, such as HIC1 and p15^INK4B, thereby facilitating cancer progression.^[73] In liver malignancies, for instance, TDG loss dysregulates demethylation pathways, enhancing oncogenic signaling through persistent methylation of suppressor loci.^[74]

Links to Neurological and Cognitive Disorders

Neurons face a high oxidative burden due to their elevated metabolic demands and constant production of reactive oxygen species (ROS), necessitating robust base excision repair (BER) to maintain genomic stability and prevent ROS-induced DNA single-strand breaks.^[75] Key BER initiators, such as the DNA glycosylases OGG1 and NEIL1, specifically recognize and excise oxidized bases like 8-oxoguanine, thereby protecting against the accumulation of mutagenic lesions that could lead to neuronal dysfunction.^[76] Deficiencies in these enzymes have been linked to increased oxidative DNA damage in the brain, underscoring BER's critical role in neuronal resilience.^[77] Impairments in BER components, particularly APE1 and DNA polymerase β (Pol β), are implicated in Alzheimer's disease (AD), where amyloid-β plaques exacerbate oxidative stress and directly inhibit BER efficiency.^[78] In AD brain tissue, reduced APE1 and Pol β expression correlates with unrepaired DNA lesions, contributing to neuronal loss and synaptic pathology.^[79] Similarly, BER decline in aging mouse models has been associated with cognitive impairments, including deficits in memory formation, highlighting the pathway's vulnerability in neurodegenerative contexts.^[80] Recent 2024 research demonstrates that BER cooperates with double-strand break repair (DSBR) pathways in the mouse brain to minimize unrepaired double-strand breaks under oxidative stress, a mechanism that fails in neurodegenerative conditions. In neurons, elevated BER activity paired with limited DSBR promotes reversible single-strand breaks, but disruptions lead to persistent genomic instability relevant to disorders like Parkinson's disease and ataxia.^[81] BER supports synaptic plasticity by repairing oxidative DNA damage at synapses, ensuring proper neuronal signaling and adaptability.^[82] Knockout models of BER enzymes, such as neuron-specific APE1 deletion, result in synaptic dysfunction, premature cognitive decline, and learning deficits, as evidenced by impaired performance in spatial memory tasks.^[83] NEIL1-deficient mice similarly exhibit reduced short-term spatial memory and altered anxiety-like behaviors, linking BER integrity to cognitive function.^[84] Base excision repair (BER) efficiency diminishes with advancing age, primarily due to reduced activity of key enzymes such as DNA glycosylases, including 8-oxoguanine DNA glycosylase (OGG1), which initiates repair of oxidative lesions like 8-oxoguanine. Studies in human leukocytes and fibroblasts demonstrate a significant age-dependent decline in OGG1 protein levels and activity, with older individuals (over 60 years) exhibiting approximately 60% lower OGG1 expression compared to younger counterparts, correlating with decreased mRNA transcription and protein stability.^[85] Additionally, oxidative damage from reactive oxygen species (ROS) accumulates in aging cells, leading to post-translational modifications and inactivation of BER proteins, including glycosylases and downstream factors like APE1, further impairing the pathway's capacity to process abasic sites and single-strand breaks.^[86] This enzymatic decline is exacerbated in mitochondria, where BER components are particularly vulnerable to age-related ROS exposure.^[87] Evidence from human and animal models underscores the extent of BER impairment in the elderly. In human diploid fibroblasts, such as IMR90 cells, BER activity decreases by 50-60% in late-passage (senescent) cultures compared to early passages, reflecting reduced glycosylase incision and overall repair kinetics.^[86] Similar reductions, ranging from 50-75%, occur in multiple tissues of aged mice (18-28 months old), including brain and liver, with pronounced effects on mitochondrial BER.^[86] This decline correlates with increased mutation load in mitochondrial DNA (mtDNA), where unrepaired oxidative lesions lead to a 3-5-fold accumulation of point mutations and deletions in aged tissues like skeletal muscle and brain, perpetuating a cycle of ROS production and genomic instability.^[87] The consequences of age-related BER decline manifest in accelerated aging phenotypes, particularly in progeroid models with BER deficiencies. For instance, mice with impaired BER, such as those overexpressing SIRT6 to rescue glycosylase activity, exhibit mitigated premature aging features like reduced lifespan and tissue dysfunction, highlighting BER's role in longevity.^[88] In natural aging, this contributes to conditions like sarcopenia, where diminished mitochondrial BER in skeletal muscle leads to mtDNA mutations, impaired bioenergetics, and loss of muscle mass and function.^[89] Frailty syndromes are similarly linked, as BER inefficiency amplifies oxidative damage, promoting systemic vulnerability and physical decline in older adults.^[89] Recent advances from 2023 onward indicate that NAD+ boosters, such as nicotinamide mononucleotide (NMN), can partially restore BER by replenishing NAD+ levels consumed by poly(ADP-ribose) polymerase 1 (PARP1), a key BER scaffold protein. In aged mice, NMN supplementation enhances PARP1 activity, reduces DNA damage accumulation, and improves repair responses, suggesting a potential mechanism to counteract age-related BER deficits without fully reversing them.^[90]

Therapeutic Targeting of BER

Inhibitors and Modulators

Base excision repair (BER) can be inhibited or modulated through small molecules and genetic interventions to disrupt the pathway's core steps, including abasic site processing and gap filling, thereby sensitizing cells to DNA damage for therapeutic gain. Inhibitors primarily target key enzymes like apurinic/apyrimidinic endonuclease 1 (APE1) or poly(ADP-ribose) polymerase (PARP), while modulators enhance specific glycosylases or polymerases to either amplify repair in protective contexts or fine-tune activity. Methoxyamine, a small-molecule aldehyde-reactive compound, inhibits BER by covalently binding to the aldehyde group at apurinic/apyrimidinic (AP) sites, preventing their processing by APE1 and trapping unrepaired lesions that lead to cytotoxicity when combined with alkylating agents. CRISPR/Cas9-mediated knockdown of APE1 similarly impairs BER by reducing the enzyme's endonuclease activity, which is essential for incising AP sites and initiating downstream repair, as demonstrated in knockout models of human cell lines where oxidative damage accumulation increases. PARP inhibitors, such as olaparib, block the long-patch subpathway of BER by inhibiting PARP1/2 activity, which is required for recruiting repair factors to single-strand breaks generated during gap-filling; this trapping mechanism overwhelms cells with persistent DNA intermediates. Modulators of BER include natural compounds like resveratrol, which enhances 8-oxoguanine DNA glycosylase (OGG1) expression and activity, promoting the removal of oxidative lesions such as 8-oxoguanine and thereby bolstering repair in response to high glucose-induced stress. Achieving selectivity for BER inhibitors is critical, as cancer cells often exhibit elevated reactive oxygen species (ROS) levels that increase reliance on BER, allowing targeted inhibition to preferentially accumulate damage in tumors while sparing normal tissues with lower ROS burdens. However, pathway redundancy—such as overlapping roles with nucleotide excision repair or alternative polymerases—poses challenges, necessitating multi-target strategies that combine BER inhibitors with agents disrupting complementary pathways to overcome compensatory mechanisms and enhance efficacy.

Applications in Precision Oncology

Base excision repair (BER) targeting has emerged as a cornerstone of precision oncology, exploiting tumor-specific deficiencies in DNA damage response (DDR) to enhance therapeutic efficacy in cancers with impaired repair pathways. By inhibiting BER components, therapies can trap unrepaired lesions, leading to synthetic lethality in genetically vulnerable tumors, particularly those with homologous recombination deficiencies like BRCA mutations. This approach builds on the success of PARP inhibitors, which indirectly burden BER, and extends to direct BER modulation for improved outcomes in solid tumors. Recent clinical translations emphasize patient stratification via genomic profiling to maximize benefit while minimizing toxicity in normal tissues.^[91] A key strategy involves BER inhibition to sensitize tumors to chemotherapy and radiation, amplifying DNA damage accumulation. For instance, APE1 inhibitors, such as APX3330, have progressed to phase I trials in advanced solid tumors, demonstrating favorable safety and response rates by blocking endonuclease activity essential for BER incision. In glioblastoma, where temozolomide resistance often stems from robust BER, preclinical data show APE1 inhibition restores sensitivity to temozolomide by preventing repair of O6-methylguanine lesions, even in mismatch repair-deficient cells. Similarly, MGMT inhibitors or promoter methylation assessment guide alkylating agent use, with unmethylated MGMT predicting poor response in glioblastoma, underscoring BER's role in precision stratification.^[92]^[93]^[94]^[95] Biomarkers of BER proficiency are increasingly used to predict prognosis and guide therapy selection. Low expression of OGG1 correlates with shorter recurrence-free and overall survival in pancreatic ductal adenocarcinoma, reflecting heightened genomic instability that may inform aggressive treatment. Likewise, reduced NEIL1 levels predict poor survival in breast cancer, while increased NEIL1 levels predict poor survival in colorectal cancer, with emerging data linking NEIL1 alterations to chemoresistance via upregulated translesion synthesis. For immunotherapy, 2025 reviews highlight BER scoring—integrating glycosylase and polymerase expression—as a predictor of immune checkpoint inhibitor response, with high BER activity associating with increased CD4+ T-cell infiltration and better outcomes in melanoma.^[96]^[69]^[97]^[98] Combination therapies leveraging BER inhibition with other DDR modulators exploit synthetic lethality in BER-deficient tumors. Pairing BER-targeted agents like PARP inhibitors with ATR or CHK1 inhibitors induces replication fork collapse in homologous recombination-deficient cells, showing preclinical synergy in ovarian and lung cancers; for example, ATR inhibition amplifies unrepaired BER intermediates into lethal double-strand breaks in BRCA-mutant models. CHK1 blockade similarly synergizes with BER disruption, enhancing apoptosis in p53-deficient tumors via unchecked replication stress. These combinations are under investigation in phase II trials, particularly for platinum-resistant ovarian cancer, where BER proficiency correlates with resistance.^[99]^[100]^[101] Emerging 2024–2025 precision approaches focus on targeted delivery to enhance specificity in BRCA-mutant cancers. Nanoparticle formulations co-delivering BER inhibitors with PARP or DNA damage agents accumulate preferentially in tumors via enhanced permeability, inhibiting repair in triple-negative breast cancer models and restoring sensitivity in BRCA-wild-type contexts. For glycosylases like OGG1, small-molecule inhibitors demonstrate synthetic lethality with BRCA1 deficiency by trapping repair intermediates, with nanoparticle encapsulation improving bioavailability and reducing off-target effects in preclinical ovarian and breast studies. These innovations, including radiation-guided nanoparticles for brain-metastatic lesions, promise to expand BER targeting beyond systemic limitations.^[102]^[103]^[104]^[105]

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Base Excision Repair, Aging and Health Span - PubMed Central - NIH
Variation among individuals at each age was observed, but overall OGG1 activity declined significantly with age (Chen et al., 2002a). “Old” IMR90 cells, a ...
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Mitochondrial DNA repair in aging and disease - PMC
The link between mtDNA damage and repair to aging, neurodegeneration, and carcinogenesis-associated processes is the subject of this review.
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SIRT6 rescues the age related decline in base excision repair in a ...
Dysfunctional base excision repair (BER) machinery may give rise to mutations and even chromosomal rearrangements, thereby contributing to aging related loss ...
[92]
Sarcopenia of aging: Underlying cellular mechanisms and ...
Furthermore, the efficiency of the main pathway for the removal of small mtDNA base modifications (base excision repair, BER) declines at different levels with ...
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NAD metabolism: Role in senescence regulation and aging - Chini
Jul 9, 2023 · NMN treatment restored the reduced PARP1 activity and DNA damage response in the old mice, indicating that these responses were dependent on ...
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Targeting base excision repair in precision oncology - PubMed
May 9, 2025 · This review discusses how targeting BER could improve treatment outcomes, particularly in DDR-defective cancers. With ongoing advancements in ...
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A Phase I study targeting the APE1/Ref-1 redox signaling protein ...
Apr 4, 2025 · This Phase 1, multicenter, open-label, dose-escalation study in advanced solid tumor was aimed at determining the recommended Phase 2 dose (RP2D) ...Missing: inhibitor 2024
[96]
New Ref-1/APE1 targeted inhibitors demonstrating improved ...
A first-generation compound, APX3330 successfully completed phase I clinical trial in adults with progressing solid tumors with favorable response rate, ...
[97]
New insights into glioblastoma resistance to temozolomide
Dec 19, 2024 · However, if APE1 is inhibited, glioblastoma cells become highly sensitive to TMZ, even if the MMR pathway is inactive. Thus, APE1 represents the ...Missing: trials | Show results with:trials
[98]
DNA repair and the contribution to chemotherapy resistance
May 26, 2025 · RAS, MYC, and cyclin E overexpression substantially elevates replication stress resulting from transcription-replication conflicts [31]. These ...Dna Damage And Repair In... · Dna Damage Response... · Targeting Dna Repair To...<|separator|>
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Mitochondrial expression of the DNA repair enzyme OGG1 improves ...
The low mitochondrial OGG1 expression group had a significantly shorter recurrence-free survival (p = 0.0080) and overall survival (p = 0.0073) rates. The Cox ...
[100]
NEIL1 drives the initiation of colorectal cancer through ... - Cell Press
Jan 3, 2024 · NEIL2 may be involved in transcription-coupled BER (TC-BER) of oxidized DNA bases, a mechanism reported in an insightful review.
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https://jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01360-x
[102]
Role of DNA repair defects in predicting immunotherapy response
Jun 29, 2020 · Here, we discuss recent studies demonstrating that biomarkers in DDR pathways may serve as potential predictors to guide the selection of patients for ICB ...
[103]
Perspectives on cancer therapy—synthetic lethal precision medicine ...
Apr 16, 2025 · [105] found that inhibition of PRMT5 selectively kills mutation-carrying cancer cells, and is particularly sensitive to tumors deficient in ...
[104]
Synthetic Lethal Combinations of DNA Repair Inhibitors and ... - NIH
Aug 23, 2025 · Treatment with the inhibitors of ATR, Chk1 and Wee1 induced a significant increase in PARP cleavage, indicative of apoptosis in the 2 lines ( ...
[105]
The synthetic lethality of targeting cell cycle checkpoints and PARPs ...
Oct 17, 2022 · PARP inhibition increases the reliance on ATR/CHK1 checkpoint signaling leading to synthetic lethality-an alternative treatment strategy for ...
[106]
Nanoparticulate drug combination inhibits DNA damage repair and ...
Jan 10, 2025 · Nanoparticulate drug combination inhibits DNA damage repair and PD-L1 expression in BRCA-mutant and wild type triple-negative breast cancer.Missing: glycosylase | Show results with:glycosylase
[107]
Cancer Vulnerabilities Through Targeting the ATR/Chk1 and ATM ...
Interestingly, simultaneous ATR and Chk1 inhibition was synthetic lethal in preclinical studies involving a variety of solid tumor models, with improved ...
[108]
OGG1: An emerging multifunctional therapeutic target for the ...
Aug 9, 2024 · OGG1 enzymatic action is crucial for DNA repair and plays a role in regulating gene transcription. Variations and functional abnormalities in ...Missing: drop | Show results with:drop
[109]
Radiation-guided nanoparticles enhance the efficacy of PARP ...
Jul 10, 2025 · We demonstrate the enhanced accumulation and efficacy of the radiation-guided P-selectin-targeted NPs in primary and brain-metastatic BRCA1-deficient tumors.Missing: delivered glycosylase 2024