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Cell cycle checkpoint

Cell cycle checkpoints are regulatory mechanisms in eukaryotic cells that act as surveillance points to ensure the proper order, integrity, and fidelity of events during the cell cycle, including DNA replication and chromosome segregation.^[1] These checkpoints monitor for cellular damage or incomplete processes and halt progression to subsequent phases until issues are resolved, thereby preventing the propagation of genetic errors that could lead to diseases such as cancer.^[2] The concept of checkpoints was introduced by Leland Hartwell in the 1970s through studies of cell division cycle (cdc) mutants in budding yeast Saccharomyces cerevisiae, and further developed by Paul Nurse in fission yeast Schizosaccharomyces pombe; Hartwell, Nurse, and Tim Hunt were awarded the 2001 Nobel Prize in Physiology or Medicine for their discoveries of key cell cycle regulators.^[3] Discovered through studies on cell cycle dependencies, they enforce sequential execution of phases like G1, S, G2, and M, with dysfunction often resulting in genomic instability or cell death.^[4] The primary checkpoints include the G1/S checkpoint, which assesses DNA integrity and cell size before replication; the G2/M checkpoint, which verifies complete DNA replication and repair prior to mitosis; and the spindle assembly checkpoint (SAC) during metaphase, which ensures accurate chromosome attachment to the mitotic spindle.^[1] Regulation at these points involves cyclin-dependent kinases (CDKs) bound to cyclins (e.g., cyclin D-CDK4/6 at G1/S, cyclin B-CDK1 at G2/M), which drive phase transitions, while inhibitors like p21, Wee1, and Cdc25 phosphatases fine-tune activity based on signals from damage sensors such as ATM/ATR kinases and their downstream effectors Chk1/Chk2.^[2] For instance, DNA damage activates p53 to induce p21, arresting the cycle for repair, whereas the SAC relies on proteins like Mad2 and Bub1 to inhibit the anaphase-promoting complex/cyclosome (APC/C) until alignment is achieved. These mechanisms are crucial for maintaining genomic stability, as their impairment—common in tumors due to mutations in p53 or checkpoint kinases—allows uncontrolled proliferation and aneuploidy.^[1] In cancer therapy, targeting checkpoints with inhibitors (e.g., CDK4/6 blockers like palbociclib or Chk1 inhibitors) exploits this vulnerability, selectively killing rapidly dividing malignant cells while sparing normal ones.^[2] Ongoing research highlights their role beyond division control, including in DNA repair pathways and responses to therapeutic agents.^[4]

Introduction

Definition and purpose

Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the fidelity and order of cell cycle events, ensuring that progression through the cycle occurs only when preceding steps are completed accurately. These regulatory points evaluate critical conditions, including DNA integrity, completion of DNA replication, cell size, and availability of nutrients or growth signals, temporarily arresting the cycle if any deficiencies are detected to allow for repair or adaptation.^[6]^[1] The fundamental purpose of cell cycle checkpoints is to safeguard genomic integrity by preventing the inheritance of damaged or incompletely replicated DNA, which could lead to mutations, chromosomal instability, or cell death. By integrating responses to internal stresses like DNA lesions and external cues such as growth factors, checkpoints coordinate cell proliferation with environmental conditions, thereby minimizing error propagation during division.^[6]^[1] These mechanisms are evolutionarily conserved across eukaryotes, reflecting their essential role in cellular homeostasis; for instance, the RAD9 protein in budding yeast mediates cell cycle arrest in response to DNA damage, while in mammals, the p53 pathway enforces similar halts to facilitate repair.^[7] The major checkpoints occur at the G1/S transition, within S phase (intra-S), at the G2/M boundary, and during spindle assembly in mitosis, positioned at key phase transitions to oversee overall cycle progression.^[1]

Historical background

The concept of regulatory controls in cell division emerged from early cytological observations in the late 19th and early 20th centuries. In 1902, Theodor Boveri conducted pioneering experiments on sea urchin embryos, demonstrating that chromosomal imbalances caused by dispermic fertilization led to abnormal multipolar mitoses and developmental failures, suggesting inherent mechanisms to ensure proper chromosome segregation during cell division.^[8] Advances in the 1970s marked a shift toward genetic and biochemical identification of cell cycle controls. Leland Hartwell's work in budding yeast (Saccharomyces cerevisiae) identified "execution points"—critical stages where cell cycle progression could be arrested—through mutations in cell division cycle (CDC) genes, such as CDC28, revealing dependencies that enforce orderly progression.^[9] Concurrently, in 1971, Yoshio Masui discovered maturation-promoting factor (MPF) in Xenopus oocytes, a cytoplasmic activity that induces meiotic maturation and highlighted regulatory factors controlling the G2/M transition.^[10] In mammalian cells, Arthur Pardee proposed the restriction point in 1974, a G1 phase commitment where cells become independent of external growth factors to proceed to S phase, based on synchronization experiments showing a post-mitotic lag before DNA replication.^[11] The 1980s built on these foundations with Paul Nurse's genetic screens in fission yeast (Schizosaccharomyces pombe), identifying the CDC2 gene as a universal cyclin-dependent kinase (CDK) that orchestrates multiple cell cycle transitions, linking yeast models to broader eukaryotic regulation.^[3] The formal concept of "checkpoints" as surveillance mechanisms arose in 1989, when Hartwell and Ted Weinert coined the term to describe DNA damage-responsive arrests in yeast, exemplified by the RAD9 gene's role in delaying cycle progression after irradiation to allow repair.^[6] These discoveries culminated in the 2001 Nobel Prize in Physiology or Medicine, awarded to Hartwell, Nurse, and Tim Hunt (for identifying cyclins) for their foundational insights into cell cycle regulation, underscoring the genetic and molecular basis of checkpoints as essential safeguards against genomic instability.^[3]

Cell cycle overview

Key phases and transitions

The eukaryotic cell cycle is divided into four main phases: G1, S, G2, and M, each with distinct functions and approximate durations in proliferating mammalian cells. The G1 phase involves cell growth and preparation for DNA replication, with a variable length that can range from several hours to days depending on external signals and cell type. The S phase is dedicated to DNA synthesis, typically lasting about 8 hours in human cells. This is followed by the G2 phase, which prepares the cell for mitosis and lasts around 4 hours. The M phase, encompassing mitosis and cytokinesis, is the shortest at approximately 1 hour. These durations contribute to a total cell cycle time of about 24 hours in rapidly dividing mammalian cells.^[12] Checkpoints operate at key transition points between these phases to ensure proper progression and fidelity. The G1/S transition marks the commitment to DNA replication, where cells assess growth factors and nutrient availability before entering S phase. The S/G2 transition verifies the completion of DNA synthesis, preventing progression with unreplicated DNA. The G2/M transition allows evaluation of DNA integrity and repair before mitosis entry. Additionally, a checkpoint at the metaphase-to-anaphase transition ensures proper chromosome alignment and attachment to the spindle before segregation. These transitions serve as critical assessment points to maintain genomic stability.^[12] Progression through these phases and transitions is primarily driven by the cyclin-dependent kinase (CDK) oscillator, where periodic activation of cyclin-CDK complexes acts as the core engine. For instance, the cyclin E-CDK2 complex promotes the G1/S transition by phosphorylating targets that initiate DNA replication. Similarly, the cyclin B-CDK1 complex drives the G2/M transition, enabling nuclear envelope breakdown and chromosome condensation. The oscillating levels of cyclins, synthesized and degraded in a phase-specific manner, ensure sequential and irreversible advancement through the cycle.^[13] Variations in the cell cycle occur across cell types and conditions. Many cells can enter a quiescent G0 phase from G1, a reversible state outside the active cycle where proliferation is halted, often in response to nutrient limitation or differentiation signals. Embryonic cells, such as those in early Xenopus laevis development, exhibit rapid cycles lacking extended G1 and G2 phases, consisting primarily of alternating S and M phases to support quick cleavage divisions. In contrast, somatic cells in adults typically include longer gap phases for growth and checkpoint surveillance, reflecting slower, more regulated proliferation.^[14]^[15]

General checkpoint mechanisms

Cell cycle checkpoints operate through a conserved molecular framework that ensures genomic integrity by detecting cellular stresses and halting progression until resolution. This framework consists of three primary components: sensors, which recognize specific aberrations such as DNA double-strand breaks (DSBs) via complexes like the MRE11-RAD50-NBS1 (MRN) or replication protein A (RPA) binding to single-stranded DNA; transducers, primarily the phosphatidylinositol 3-kinase-related kinases (PIKKs) ATM and ATR, which are activated by these sensors to amplify the signal; and effectors, such as CDK inhibitors including p21^CIP1 and Wee1 kinase, which enforce arrest by targeting cyclin-dependent kinases (CDKs).^[16]^[17] These components form a sensor-effector logic that is broadly shared across checkpoints, allowing rapid response to threats like DNA damage or replication stress during interphase transitions.^[18] Signaling cascades initiate upon sensor activation, where ATM phosphorylates targets in response to DSBs, while ATR responds to replication fork stalling, both leading to a series of phosphorylation events that propagate the signal. For instance, ATM and ATR phosphorylate and activate downstream kinases Chk2 and Chk1, respectively, which in turn inhibit Cdc25 phosphatases and promote the expression or stabilization of CDK inhibitors like p21, thereby preventing cyclin-CDK complex activation required for phase transitions.^[16] Additionally, ubiquitin-mediated degradation plays a key role, with the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase broadly contributing to checkpoint enforcement by targeting cyclins and other regulators for proteasomal degradation, maintaining low CDK activity during stress.^[19] This phosphorylation-dominated cascade, often amplified by positive feedback loops involving histone modifications like γ-H2AX, ensures robust inhibition of cell cycle progression.^[20] Checkpoint recovery mechanisms restore progression once the stress is resolved, primarily through phosphatase-mediated dephosphorylation that reactivates key regulators. For example, protein phosphatase 2A (PP2A) and other phosphatases counteract Chk1/Chk2 activity, allowing Cdc25 phosphatases to resume dephosphorylating and activating CDKs, thus reversing arrest.^[21] APC/C activity is also modulated during recovery to stabilize necessary cyclins. The universal outcomes of these mechanisms include temporary cell cycle arrest to facilitate repair processes, such as homologous recombination or non-homologous end joining, or induction of apoptosis via effectors like p53 if damage proves irreparable.^[16] Cross-talk between checkpoints enhances robustness; for instance, failure to resolve issues at the G1/S transition can propagate unrepaired damage, activating downstream G2/M arrest through persistent ATM/ATR signaling.^[18]

G1/S checkpoint

Restriction point regulation

The restriction point (R-point) represents an irreversible commitment to the cell cycle that occurs in late G1 phase, approximately 2-3 hours before the onset of S phase, beyond which cells proceed to division independent of external growth factors.^[22] This checkpoint ensures cells only replicate DNA when conditions are favorable for proliferation, integrating signals from mitogens, nutrients, and internal status to prevent inappropriate division. Originally described in mammalian fibroblasts, the R-point marks the transition from mitogen-dependent progression to an autonomous cell cycle trajectory. Central to R-point regulation is the retinoblastoma protein (Rb)-E2F pathway, where Rb initially represses E2F transcription factors to block expression of S-phase genes. Hyperphosphorylation of Rb sequentially occurs first via cyclin D bound to CDK4 or CDK6, initiated by growth factor signaling, which partially inactivates Rb and allows limited E2F activity.^[23] This is followed by cyclin E-CDK2-mediated hyperphosphorylation, fully releasing E2F to drive transcription of cyclins, DNA replication factors, and other proliferation genes, committing the cell past the R-point.^[24] Growth factors such as platelet-derived growth factor (PDGF) activate this cascade by inducing immediate-early genes like Myc, which in turn upregulates cyclin D expression and sustains mitogenic signaling through early G1.^[25] At the R-point, cells assess multiple criteria, including attainment of sufficient size through accumulated biomass, availability of nutrients like amino acids sensed via the mTOR pathway, and absence of DNA damage. Amino acid sufficiency activates mTORC1, promoting protein synthesis and cyclin D translation to support Rb inactivation and G1 progression.^[26] In response to DNA damage, p53 transcriptionally induces p21 (CDKN1A), which inhibits CDK4/6 and CDK2 complexes, maintaining Rb in its active hypophosphorylated state to enforce G1 arrest. Failure to meet these thresholds, such as mitogen withdrawal before the R-point, directs cells to quiescence in G0 phase, where they reversibly exit the cycle without DNA replication. Successful passage, however, locks cells into completing the division, even if growth signals are later removed, underscoring the R-point's role as a unidirectional gatekeeper.^[27]

DNA damage response integration

The G1/S checkpoint integrates DNA damage signals detected during the G1 phase, primarily from ionizing radiation-induced single-strand breaks (SSBs) and double-strand breaks (DSBs), as well as ultraviolet (UV) radiation-induced lesions such as cyclobutane pyrimidine dimers and 6-4 photoproducts.^[28]^[29] These damages are sensed by the MRN complex (MRE11-RAD50-NBS1) coupled with ATM kinase for DSBs, or by RPA-coated ssDNA gaps activating ATR kinase for UV lesions and SSBs.^[30]^[31] This detection halts cell cycle progression at the restriction point, preventing entry into S phase until repair is assessed. The primary pathway for damage integration involves ATM activation upon DSB recognition, leading to autophosphorylation and subsequent phosphorylation of p53 at serine 15, which disrupts the p53-MDM2 interaction and stabilizes p53 by inhibiting its ubiquitination and degradation.^[32]^[33] Stabilized p53 transactivates the cyclin-dependent kinase inhibitor p21 (encoded by CDKN1A), which binds and inhibits cyclin E-CDK2 complexes, thereby maintaining retinoblastoma protein (Rb) in its hypophosphorylated state to repress E2F-dependent transcription of S-phase genes.^[34]^[35] For UV-induced lesions, ATR similarly contributes to p53 stabilization via Chk1-mediated signaling, though with slower kinetics in G1 compared to DSB responses.^[36] This p53-p21 axis enforces a prolonged G1 arrest, allowing time for DNA repair. p53-independent pathways provide rapid checkpoint enforcement, particularly for milder damage, through ATM-Chk2 signaling that phosphorylates and promotes ubiquitin-mediated degradation of Cdc25A phosphatase, thereby preventing CDK2 activation and S-phase entry without relying on transcriptional changes.^[37]^[38] Chk2 activation occurs within minutes of damage and supports G1 arrest in p53-deficient cells, though it is less sustained than the p53-dependent response.^[39] The checkpoint sensitivity is high, with studies showing that even a single DSB can trigger p53 pulses and G1 arrest in human cells, while the probability and duration of arrest scale linearly with damage levels.^[40] This arrest coordinates repair mechanisms suited to G1 phase conditions, including non-homologous end joining (NHEJ) for DSBs—mediated by Ku70/80, DNA-PKcs, XRCC4, and ligase IV—and base excision repair (BER) for UV-induced base lesions via glycosylases like OGG1 and APE1 endonuclease.^[41]^[42] If damage persists or is extensive, p53 shifts from arrest to apoptosis by upregulating pro-apoptotic effectors such as Bax and Bak, which oligomerize to permeabilize the mitochondrial outer membrane and release cytochrome c.^[43]^[44] This threshold-dependent decision ensures elimination of irreparably damaged cells, preserving genomic integrity.

S-phase checkpoint

Replication stress detection

Replication stress in the S phase arises from various impediments that slow or stall DNA replication forks, including depletion of deoxynucleotide triphosphates (dNTPs), topological constraints such as torsional stress ahead of the fork, and exposure to exogenous agents like hydroxyurea, which inhibits ribonucleotide reductase and induces dNTP exhaustion.^[45]^[46] These stresses lead to fork stalling or collapse, generating single-stranded DNA (ssDNA) regions that serve as primary signals for checkpoint activation.^[45] The primary sensors for replication stress involve the recognition of ssDNA coated by replication protein A (RPA), which recruits the ATR-ATRIP complex to these sites.^[47] Independently, the Rad17-RFC clamp loader recognizes primer-template junctions and loads the 9-1-1 complex (comprising Rad9, Hus1, and Rad1) onto the DNA.^[48] TopBP1 is then recruited to RPA-ssDNA in an ATRIP-dependent manner and interacts with the 9-1-1 complex to fully activate ATR kinase activity at stalled forks.^[49]^[50] Upon activation, ATR phosphorylates the checkpoint kinase Chk1 at serine 345, enabling Chk1 to phosphorylate Cdc25A phosphatase, which promotes its ubiquitin-mediated degradation.^[51] This degradation inhibits Cdc25A's ability to activate CDK2, thereby preventing new origin firing and controlling replication progression.^[52]^[53] The outcomes of this detection include slowed progression of existing replication forks to conserve resources, suppression of late-firing replication origins to avoid exhaustion, and prevention of premature entry into mitosis by maintaining low CDK activity.^[54] Additionally, the Fanconi anemia (FA) pathway is engaged to stabilize stalled forks through monoubiquitination of FANCD2-FANCI, facilitating fork restart and preventing collapse into double-strand breaks.^[55]^[56] This intra-S phase mechanism operates dynamically throughout S phase, distinguishing it from G1/S commitment checkpoints by focusing on ongoing replication fidelity rather than initial entry decisions.^[57]

Signaling and enforcement

The intra-S-phase checkpoint signaling pathway is primarily orchestrated by the ataxia-telangiectasia and Rad3-related (ATR) kinase, which detects replication stress through persistent single-stranded DNA (ssDNA) coated with replication protein A (RPA). Upon activation, ATR phosphorylates and activates the effector kinase checkpoint kinase 1 (Chk1), with Claspin serving as a critical adaptor protein that facilitates this phosphorylation event by recruiting Chk1 to ATR at stalled replication forks.^[58]^[57] Chk1 then targets multiple downstream effectors to enforce checkpoint responses, including the phosphorylation of the phosphatase Cdc25A, which marks it for ubiquitin-mediated degradation and thereby prevents excessive firing of replication origins during ongoing stress.^[52] This degradation of Cdc25A limits the activation of cyclin-dependent kinases (CDKs), ensuring controlled replication progression.^[59] Enforcement of the intra-S checkpoint occurs through dual mechanisms: direct inhibition of S-phase progression and facilitation of DNA repair. Chk1-mediated suppression of Cdc25A reduces cyclin A-CDK2 activity, which in turn slows replication fork elongation and prevents untimely origin activation, thereby conserving resources for repair at stalled sites.^[57] Concurrently, the pathway promotes homologous recombination (HR) repair by stabilizing stalled forks and recruiting repair factors, such as through ATR-dependent phosphorylation of BRCA1, which supports strand invasion and resolution of double-strand breaks arising from fork collapse.^[58] For specific lesions like those induced by ultraviolet (UV) radiation, the checkpoint also enables translesion synthesis (TLS) by promoting monoubiquitination of proliferating cell nuclear antigen (PCNA), allowing recruitment of error-prone DNA polymerases to bypass damage without halting replication entirely.^[60] If replication stress remains unresolved, the intra-S checkpoint signals cross-talk to the G2/M checkpoint via persistent ssDNA accumulation, which sustains ATR-Chk1 activation and delays mitotic entry to prevent inheritance of under-replicated DNA.^[57] This coordination ensures genomic stability across phases, with unresolved UV-induced lesions particularly reliant on TLS to avoid propagating damage into G2.^[60] Experimental studies in human cells, such as U-2 OS osteosarcoma lines, demonstrate that pharmacological inhibition of ATR (e.g., with VE-821) during replication stress leads to unchecked origin firing, exhaustion of RPA pools, accumulation of under-replicated DNA regions, and subsequent pan-nuclear replication catastrophe culminating in mitotic cell death.^[61] These findings highlight ATR's essential role in preventing catastrophic genome instability.^[62] The checkpoint remains active throughout S phase until replication is largely complete, at which point fork recovery predominates and progression to G2 is permitted, as evidenced by DNA combing assays showing slowed but eventual completion of replication in stressed human cells.^[63] Recent studies as of 2025 have further shown that nucleosomes serve as a crucial target for the intra-S phase checkpoint, with the ubiquitin E3 ligase Brl2 being regulated to protect stalled replication forks from collapse under stress.^[64]

G2/M checkpoint

Core activation pathways

The G2/M checkpoint is primarily activated by two major signaling pathways that detect DNA damage and unreplicated DNA, preventing the activation of cyclin B-CDK1 (also known as MPF) to block entry into mitosis.^[65] For DNA double-strand breaks (DSBs), the ataxia-telangiectasia mutated (ATM) kinase is recruited to damage sites via the MRN complex (Mre11-Rad50-Nbs1), where it undergoes autophosphorylation at Ser1981 to initiate signaling.^[65] ATM then phosphorylates and activates the checkpoint kinase Chk2 at Thr68, promoting its dimerization and downstream propagation.^[65] In contrast, for single-stranded DNA (ssDNA) arising from replication stress or other lesions, the ataxia-telangiectasia and Rad3-related (ATR) kinase is activated by RPA-coated ssDNA and the Rad9-TopBP1 complex, leading to phosphorylation and activation of Chk1.^[65] These activated kinases target key regulators of CDK1 activity to enforce cell cycle arrest. Chk1 and Chk2 phosphorylate Cdc25C phosphatase at Ser216, creating a binding site for 14-3-3 proteins that sequester Cdc25C in the cytoplasm, preventing its dephosphorylation and activation of nuclear CDK1.^[66] Concurrently, Chk1 promotes the activation of Wee1 kinase, which phosphorylates CDK1 at Tyr15 (and Thr14), maintaining it in an inactive state and inhibiting the G2/M transition.^[65] These mechanisms collectively inhibit the cyclin B-CDK1 complex, allowing time for DNA repair, with arrest durations typically ranging from 4 to 24 hours depending on damage severity and repair efficiency.^[67] Detection of unreplicated DNA at the G2/M transition involves the Rad17-RFC clamp loader complex, which recognizes DNA structures at stalled forks and loads the Rad9-Hus1-Rad1 (9-1-1) heterotrimeric sliding clamp onto chromatin.^[68] The 9-1-1 complex then facilitates ATR activation and recruitment of additional factors, including Polo-like kinase 1 (Plk1) and Aurora kinases, which provide feedback amplification to sustain the checkpoint signal until replication completes.^[68] The checkpoint response bifurcates into p53-dependent and p53-independent pathways for arrest duration and enforcement. In the p53-dependent pathway, DNA damage stabilizes p53, which transcriptionally induces p21 (CDKN1A), a CDK inhibitor that directly binds and inhibits cyclin B-CDK1, promoting prolonged G2 arrest to facilitate repair.^[69] Conversely, the p53-independent pathway relies on rapid post-translational modifications, such as Chk1/Chk2-mediated Cdc25 inhibition and Wee1 activation, to swiftly block CDK1 without transcriptional changes, providing an immediate barrier to mitotic entry.^[69] In Xenopus oocytes, which are naturally arrested at G2 of meiosis I, the core activation pathway involves inactivation of MPF (cyclin B-CDK1) through the Mos-MAPK pathway, where progesterone-induced Mos synthesis activates MAPK to inhibit Cdc25 and enhance Myt1/Wee1-mediated inhibitory phosphorylation of CDK1, preventing premature maturation until fertilization cues.^[70]

Bistability and mathematical modeling

The G2/M checkpoint displays bistability, maintaining the cell in one of two stable states—interphase or mitosis—due to positive feedback in CDK1 activation. This arises primarily from the double-positive feedback loop between cyclin B-CDK1 and the phosphatase Cdc25, coupled with a double-negative feedback loop between cyclin B-CDK1 and the kinase Wee1, which collectively generate ultrasensitive, switch-like responses to ensure decisive progression into mitosis.^[71] Hysteresis in the G2/M transition reinforces this bistability by creating distinct activation and deactivation thresholds for CDK1; a higher level of cyclin B-CDK1 activity is required to trigger mitotic entry than to promote exit, rendering the commitment to mitosis irreversible and preventing erratic oscillations that could compromise genomic integrity.^[72] The foundational mathematical framework for these dynamics was established in the Novak-Tyson model of 1993, which employs ordinary differential equations to simulate M-phase control in Xenopus systems. Key interactions are captured, for example, in the equation for active cyclin B-CDK1 (MPF) formation:

\frac{d[\text{active CDK1}]}{dt} = k_1 [\text{cyclin B}] [\text{inactive CDK1}] - k_2 [\text{Wee1}] [\text{active CDK1}] + k_3 [\text{Cdc25}] [\text{active CDK1}],

where the first term represents cyclin B binding to inactive CDK1, the second inhibitory phosphorylation by Wee1, and the third activating dephosphorylation by Cdc25; numerical simulations reveal abrupt transitions and hysteresis, with steady-state bifurcations illustrating the dual stable states. Subsequent refinements in the 2000s incorporated updated parameterizations from experimental data, enhancing predictive accuracy for cyclin oscillations.^[73] This model's predictions were experimentally validated using cycling Xenopus egg extracts, where MPF activation occurs in an all-or-none manner, exhibiting hysteresis with separate thresholds for interphase-to-mitosis (∼30% cyclin B) and mitosis-to-interphase transitions (∼10% cyclin B), thereby demonstrating the checkpoint's robustness to molecular noise and variable stimuli.^[72] Post-2010 extensions to these models integrate Plk1-mediated positive feedback loops, where Plk1 amplifies Cdc25 activation and Wee1 inhibition in parallel to CDK1, improving resistance to stochastic fluctuations and ensuring synchronized G2/M entry under physiological variability.^[74]

Spindle assembly checkpoint

Metaphase surveillance

The spindle assembly checkpoint (SAC) during metaphase primarily monitors the attachment of kinetochores to microtubules from opposite spindle poles, ensuring all chromosomes achieve bi-orientation before anaphase onset. Unattached kinetochores serve as the key sensors, generating a diffusible "wait-anaphase" signal that inhibits the anaphase-promoting complex/cyclosome (APC/C). This signal is initiated by the recruitment of the Mad1-Mad2 complex to unattached kinetochores, where Mad1 acts as a template to catalyze a conformational change in Mad2 from an open (O-Mad2) to a closed (C-Mad2) state. The C-Mad2 form then binds Cdc20, a co-activator of APC/C, forming the core of the mitotic checkpoint complex (MCC) that sequesters Cdc20 and prevents premature ubiquitin-mediated degradation of securin and cyclin B.^[75] Key components of this surveillance machinery include the kinases BubR1, Bub3, and Mps1, which are rapidly recruited to unattached kinetochores to amplify the signal. Mps1 phosphorylates kinetochore proteins to promote Mad1-Mad2 localization, while BubR1 and Bub3 form a complex that further inhibits Cdc20 by integrating into the MCC. Tension across bi-oriented kinetochores is sensed through Aurora B kinase, which phosphorylates substrates like Ndc80/Hec1 when attachments lack stability, leading to microtubule detachment and error correction. This mechanism distinguishes between mere occupancy and proper bipolar attachment, ensuring accurate chromosome segregation.^[76] In mammalian cells, SAC-mediated metaphase surveillance typically lasts 20-30 minutes until all chromosomes are bi-oriented, after which the checkpoint is silenced to allow anaphase progression. Silencing involves the phosphatases PP1 and PP2A-B56, which dephosphorylate kinetochore components such as Knl1 and Mps1, stripping SAC proteins from attached kinetochores and disassembling the MCC. This process is tightly regulated to prevent premature exit, with PP1 recruitment to Knl1 being essential for efficient signal termination.^[77]^[78] The SAC surveillance mechanism is highly conserved evolutionarily, from budding yeast (where Mps1 was first identified) to humans, reflecting its fundamental role in genome stability. In yeast, MPS1 mutants fail to arrest in response to spindle defects, a phenotype mirrored in human cells depleted of Mps1, underscoring the pathway's preservation across eukaryotes. Beyond monitoring, the SAC facilitates error correction by promoting detachment of improper attachments, such as syntelic or merotelic orientations, through Aurora B-mediated destabilization under low tension.^[79] If metaphase surveillance detects persistent unattached kinetochores, the resulting prolonged arrest (beyond several hours) activates apoptotic pathways, often via sustained cyclin B-Cdk1 activity leading to caspase activation and cell death. This safeguard eliminates cells with irreparable segregation errors, preventing aneuploidy propagation.^[80]

Anaphase-promoting complex regulation

The anaphase-promoting complex (APC/C), also known as the cyclosome, is a multi-subunit E3 ubiquitin ligase that plays a central role in mitotic progression by targeting specific substrates for proteasomal degradation. In early mitosis, APC/C is activated by its co-activator Cdc20 to ubiquitinate securin (Pds1p in budding yeast) and cyclin B, which are key inhibitors of anaphase onset and mitotic exit, respectively. Later in mitosis, after Cdc20 dissociation, APC/C binds the co-activator Cdh1 to sustain degradation of additional substrates during G1 phase.^[81] The spindle assembly checkpoint (SAC) exerts precise control over APC/C activity to prevent premature anaphase until all kinetochores achieve bipolar microtubule attachment. Central to this inhibition is the mitotic checkpoint complex (MCC), which includes the conformational change in Mad2 that binds Cdc20, forming a Mad2-Cdc20 inhibitory complex that directly blocks APC/C-Cdc20 association and ubiquitination activity. This inhibition persists until all kinetochores are satisfied, at which point SAC silencing occurs through dynein-mediated stripping of MCC components from kinetochores along microtubules toward spindle poles, thereby releasing Cdc20 for APC/C activation.^[82]^[83] APC/C regulation involves intricate phosphorylation dynamics to ensure timely activation. During prometaphase, CDK1-cyclin B phosphorylates APC/C subunits (such as Apc1 and Cdc16) and Cdc20, promoting conformational changes that enable Cdc20 binding and APC/C-Cdc20 activity toward securin and cyclin B. In late mitosis, dephosphorylation by the phosphatase Cdc14 (in yeast) or analogous phosphatases in mammals removes these inhibitory phosphates, facilitating Cdc20 release and subsequent Cdh1 binding to APC/C for complete mitotic exit.^[84]^[85] Upon SAC satisfaction, APC/C-Cdc20-mediated degradation of securin relieves inhibition of separase, allowing separase to cleave the cohesin subunit Scc1 (Rad21 in humans) and thereby trigger sister chromatid separation at anaphase onset. Concurrently, cyclin B ubiquitination and degradation by APC/C inactivate CDK1, lowering mitotic CDK1 activity to promote mitotic exit, chromosome decondensation, and cytokinesis.^[86]^[81] Evidence for SAC-APC/C regulation has been established in model organisms. In budding yeast (Saccharomyces cerevisiae), cdc20 temperature-sensitive mutants arrest in metaphase with high cyclin B levels and undivided chromosomes, demonstrating Cdc20's essential role in APC/C activation for anaphase progression. In human cells, treatment with taxol (paclitaxel), which disrupts microtubule dynamics and activates the SAC, induces prolonged metaphase arrest by sustaining MCC inhibition of APC/C, highlighting the checkpoint's enforcement in mammalian systems.^[87]^[88]

Checkpoints in pathology

Dysregulation in cancer

Dysregulation of cell cycle checkpoints is a hallmark of cancer, primarily through mutations or losses in key components that impair surveillance mechanisms, leading to genomic instability and uncontrolled proliferation. Mutations in the TP53 gene, which encodes the p53 protein central to the G1/S checkpoint, occur in approximately 50% of human cancers and disable DNA damage-induced arrest, allowing cells with genomic errors to progress into S phase. Similarly, mutations in the APC gene, a regulator of the anaphase-promoting complex/cyclosome (APC/C) involved in the spindle assembly checkpoint (SAC), are prevalent in colorectal cancers and promote chromosomal instability (CIN) by disrupting mitotic progression and chromosome segregation. These defects collectively erode the cell's ability to halt the cycle at critical points, fostering tumorigenesis. Loss of checkpoint integrity manifests in specific pathological roles, such as SAC failure causing aneuploidy through erroneous chromosome segregation during mitosis, a feature observed in many solid tumors. Defects in ATR and Chk1 kinases, which enforce the intra-S and G2/M checkpoints, exacerbate replication errors by failing to stabilize stalled forks under stress, contributing to mutations and copy number alterations in cancers like ovarian and pancreatic types. Oncogenic activation, such as RAS mutations, induces replication stress that overwhelms the intra-S checkpoint, driving hyperproliferation and genomic chaos in lung and colorectal cancers. Illustrative examples include BRCA1/2 loss, which impairs homologous recombination (HR) repair during S/G2 phases and allows bypass of the G2/M checkpoint, leading to unrepaired double-strand breaks and heightened CIN in breast and ovarian cancers. In viral oncogenesis, human papillomavirus (HPV) E7 protein inactivates the Rb tumor suppressor, abrogating the G1/S restriction point and promoting unchecked entry into S phase in cervical cancers. These disruptions result in hyperproliferation and contribute to therapy resistance; for instance, absent G2 arrest diminishes the efficacy of cisplatin by preventing repair of replication-associated damage. Epidemiological evidence underscores checkpoint genes as tumor suppressors, with germline TP53 mutations causing Li-Fraumeni syndrome, a heritable condition conferring a lifetime cancer risk exceeding 90% due to defective G1/S and G2/M surveillance across multiple tissues. Such losses also enable synthetic lethality, where HR defects from BRCA1/2 or related mutations sensitize cells to PARP inhibition by preventing alternative repair of replication-induced lesions, a concept validated in preclinical models of HR-deficient tumors.

Therapeutic implications

Targeting cell cycle checkpoints has emerged as a promising strategy in cancer therapy, primarily by exploiting the dependency of tumor cells on these mechanisms to survive DNA damage and replication stress, while many cancers harbor defects in upstream regulators like p53. Inhibitors of checkpoint kinases such as CHK1 and CHK2 sensitize cancer cells to DNA-damaging agents by preventing repair and cell cycle arrest, leading to mitotic catastrophe. For instance, prexasertib, a selective CHK1/CHK2 inhibitor, has demonstrated monotherapy activity in platinum-resistant high-grade serous ovarian cancer, with durable responses observed in BRCA wild-type patients. Similarly, Aurora B inhibitors like barasertib disrupt the spindle assembly checkpoint (SAC) by impairing chromosome alignment and cytokinesis, inhibiting growth in small cell lung cancer models both in vitro and in vivo, particularly those with cMYC amplification. These agents highlight how checkpoint inhibition can selectively target proliferating tumor cells over quiescent normal tissues. Checkpoint abrogation, particularly of the G2/M checkpoint, enhances the efficacy of radiotherapy and chemotherapy by forcing cells with unrepaired DNA damage into mitosis, resulting in cell death. Caffeine, a classic ATM/ATR inhibitor, overrides G2/M arrest induced by ionizing radiation, radiosensitizing tumor cells without affecting ATM/ATR kinase activity directly but by disrupting downstream signaling. More selectively, ATR inhibitors like AZD6738 abrogate replication stress checkpoints, potentiating radiotherapy in various solid tumors; as of 2025, it is in phase II trials combined with olaparib for IDH1/2-mutated advanced solid tumors, showing promising antitumor activity through enhanced DNA damage and immune activation. Combinations with DNA-damaging agents further amplify this effect; for example, low-dose gemcitabine paired with CHK1 inhibitors like SRA737 or LY2880070 induces synergistic cytotoxicity in pancreatic ductal adenocarcinoma and high-grade serous ovarian cancer by exacerbating replication fork collapse and apoptosis, especially in p53-deficient tumors that rely heavily on CHK1 for survival. Despite these advances, therapeutic targeting of checkpoints faces significant challenges, including toxicity to proliferating normal cells such as bone marrow progenitors, which can lead to myelosuppression and limit dosing. Adaptive resistance also arises through alternative pathways, such as upregulated DNA repair or checkpoint redundancy, necessitating combination strategies to overcome tumor heterogeneity. Emerging approaches include PROTACs for CDK degraders, which induce proteasomal degradation of cell cycle regulators like CDK4/6 and CDK9, showing preclinical efficacy in overcoming resistance in breast and prostate cancers by more completely ablating checkpoint control. Post-2020 developments in SAC-targeted therapies leverage induced aneuploidy to activate cGAS-STING signaling, enhancing antitumor immunity; mitotic inhibitors that weaken the SAC promote micronuclei formation and immunogenic cell death, synergizing with checkpoint blockade in aneuploid tumors as predictive biomarkers for immunotherapy response.

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