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G1 phase

The G1 phase, also known as the first gap phase or Gap 1, is the initial stage of interphase in the eukaryotic cell cycle, occurring immediately after mitosis and before DNA synthesis in the S phase.^[1] During this period, the newly divided daughter cell grows in size, duplicates its cellular contents such as proteins and organelles (including ribosomes and mitochondria), and evaluates environmental and internal conditions to determine whether to proceed with division.^[1]^[2] The duration of G1 varies widely by cell type and conditions, often lasting about 11 hours in proliferating human cells within a typical 24-hour cycle, though it can be shorter (2–10 hours) or extended indefinitely if the cell enters a quiescent G0 state.^[2]^[3] Progression through G1 is tightly regulated by extracellular growth factors, such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), which activate signaling pathways like Ras/Erk and PI3K/Akt to induce expression of cyclin D and activate cyclin-dependent kinases (CDK4/6).^[2] These complexes phosphorylate the retinoblastoma protein (Rb), releasing E2F transcription factors to promote genes required for S-phase entry, while inhibitors like p21Cip1 and p27Kip1 can halt progression if conditions are unfavorable.^[2] A key regulatory point, known as the restriction point in mammalian cells, occurs in late G1, committing the cell irreversibly to division once sufficient growth and nutrient availability are confirmed, thereby preventing replication of damaged DNA.^[1]^[2] Dysregulation of G1 controls, such as overexpression of cyclins or loss of checkpoint proteins, is implicated in uncontrolled proliferation seen in cancers.^[2]

Fundamentals

Definition and Position in Cell Cycle

The G1 phase, also known as the gap 1 phase, represents the initial stage of the eukaryotic cell cycle, occurring immediately after the completion of mitosis (M phase) and before the onset of DNA synthesis in the S phase. During G1, the daughter cells from the preceding division primarily focus on growth, increasing in size through protein synthesis and organelle duplication while performing routine cellular maintenance and metabolic activities. This phase allows the cells to restore their mass and prepare for the demands of subsequent replication and division.^[4] Within the standard eukaryotic cell cycle, which comprises four principal phases—G1, S (DNA synthesis), G2 (gap 2), and M (mitosis)—the G1 phase holds a pivotal position as the first post-division interval following cytokinesis. It serves as the primary commitment period where cells assess environmental conditions and internal readiness before irrevocably progressing toward DNA replication, distinguishing it as the foundational growth stage in the cycle. Entry into G1 is contingent upon successful exit from mitosis, initiated by the inactivation of the cyclin B-CDK1 complex, which triggers mitotic spindle disassembly, chromosome decondensation, nuclear envelope reformation, and the finalization of cytokinesis to yield two independent daughter cells.^[5]^[6] The characteristics and duration of the G1 phase exhibit significant variability depending on cell type and physiological context. In rapidly proliferating embryonic cells, such as mouse embryonic stem cells, G1 is notably brief, often lasting just a few hours and comprising only about 15% of the cell cycle, to support swift developmental progression. In contrast, many terminally differentiated cells, including neurons, extend G1 indefinitely by transitioning into a quiescent G0 state, where they halt proliferation to maintain specialized functions without re-entering the active cycle. In early embryonic stages of many invertebrates and amphibians, such as sea urchins and Xenopus laevis, the G1 phase is absent, allowing for rapid synchronous cleavages.^[7]^[8]^[9]

Duration and Variability

The G1 phase in mammalian somatic cells typically lasts 6 to 12 hours, comprising a substantial portion of the overall cell cycle, which averages around 24 hours in rapidly proliferating human cells such as fibroblasts or epithelial cells. For instance, in HeLa cells, a common model for human cervical cancer, the G1 phase occupies approximately 6-7 hours within an 18-20 hour cycle.^[10] This duration allows cells to assess environmental conditions and prepare for DNA replication. However, the length of G1 is highly variable across cell types and physiological states; in early embryonic cells of organisms like Xenopus laevis or sea urchins, G1 is effectively absent, supporting rapid cleavage divisions with cycle times of approximately 30 minutes during development.^[11] In contrast, differentiated cells such as adult hepatocytes in the liver often remain in an extended G1-like state (or G0 quiescence) for days to over a year between divisions, reflecting their low proliferative rate unless stimulated by injury or regeneration. Several factors influence the duration of the G1 phase, including nutrient availability, cell type, and external signals such as mitogens. In nutrient-rich conditions, cells progress more quickly through G1, whereas starvation or limited amino acids can prolong it by activating stress responses that halt cycle progression. Proliferative cell types, like those in intestinal epithelium, maintain a shorter G1 compared to differentiated or quiescent cells, such as neurons, where G1 extension prevents inappropriate division. Mitogenic growth factors, including epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), accelerate G1 by stimulating signaling cascades that promote cyclin expression and checkpoint passage. The variability in G1 length shows evolutionary conservation tied to organismal complexity and the need for division decision-making. In unicellular eukaryotes like budding yeast (Saccharomyces cerevisiae), G1 is brief, averaging 20 to 30 minutes (around 37 minutes for haploid daughter cells), enabling rapid adaptation to fluctuating environments without extensive pre-division checks. In more complex multicellular organisms like mammals, the extended G1 duration facilitates integration of multiple signals to ensure proper tissue homeostasis and prevent errors like uncontrolled proliferation. The total cell cycle time can be approximated as the sum of G1, S, G2, and M phase durations, with G1 often contributing the most variability due to its regulatory flexibility. G1 phase length is commonly measured in cell populations using techniques like incorporation of thymidine analogs (e.g., bromodeoxyuridine or BrdU) to label S-phase entry, combined with flow cytometry to quantify DNA content and distinguish G1 cells (2N DNA) from those in other phases. This approach allows estimation of phase durations by tracking the fraction of labeled cells over time, providing insights into cycle kinetics without requiring single-cell imaging. Alternative methods, such as cumulative EdU labeling, further refine measurements by saturating S-phase incorporation to calculate absolute G1 and G2 lengths in asynchronous cultures.

Cellular Processes

Cell Growth and Biosynthesis

During the G1 phase, cells undergo significant anabolic expansion to accumulate biomass necessary for subsequent division, primarily through heightened protein synthesis that supports the doubling of cellular mass. This involves upregulated transcription and translation of housekeeping genes, which maintain essential cellular functions, as well as genes encoding ribosomal components and metabolic enzymes critical for energy production and structural integrity.^[2] As a result, the cell's protein content approximately doubles, ensuring each daughter cell inherits sufficient material for viability post-mitosis.^[12] Nutrient uptake and metabolic pathways are activated to fuel this growth, with enhanced glycolysis providing ATP and biosynthetic precursors, increased amino acid transport supplying building blocks for protein assembly, and elevated lipid synthesis generating membranes and signaling molecules. The mTOR pathway plays a key role in coordinating these processes, promoting anabolic metabolism and biomass buildup in response to nutrient availability without initiating DNA replication.^[13] These metabolic shifts ensure a steady influx of carbon, nitrogen, and energy sources to sustain the biosynthetic demands of G1.^[14] Parallel to protein production, cells expand their RNA and nucleotide pools to prepare for later phases, including robust synthesis of ribosomal RNA (rRNA) in the nucleolus via RNA polymerase I activity. This rRNA production increases during G1 following nucleolar reassembly in early G1, supporting ribosome biogenesis and amplifies translational capacity without involving DNA synthesis. Overall, these activities lead to a roughly twofold increase in cell volume, underscoring the scale of biosynthetic investment in G1.^[15] This biomass accumulation is coordinated with organelle biogenesis to maintain cellular homeostasis.^[2]

Organelle Synthesis and Preparation for S Phase

During the G1 phase, cells initiate the biogenesis of key organelles to support subsequent cell cycle stages, with centrosome duplication occurring early to ensure proper spindle formation in mitosis. In somatic mammalian cells, the earliest events of centrosome replication are recognizable during G1, where the single centrosome from the previous mitosis begins to split and form daughter structures, coordinated by G1-specific cyclin-dependent kinases (CDKs) that phosphorylate regulatory proteins such as nucleophosmin (NPM), CP110, and Mps1 to license and initiate this process.^[16]^[17] This duplication is tightly linked to the cell cycle to prevent overduplication, ensuring each daughter cell inherits one centrosome.^[18] Mitochondrial biogenesis also ramps up in G1 to meet the increased energy demands of DNA replication and cell growth, involving fusion events that elongate and interconnect the fragmented mitochondrial network inherited from mitosis. Entry into G1 is associated with a burst of mitochondrial activity, where fusion mediated by mitofusins interconnects mitochondria, allowing for biogenesis and even distribution to support ATP production for S phase.^[19]^[20] This dynamic balance of fission and fusion is essential for maintaining mitochondrial function throughout the cell cycle.^[21] A critical preparation for S phase occurs through the assembly of pre-replication complexes (pre-RCs) at DNA replication origins, known as replication licensing, which ensures DNA is replicated exactly once per cycle. In G1, the origin recognition complex (ORC) binds to replication origins, recruiting Cdc6 and Cdt1 to load the MCM2-7 helicase hexamers, forming the pre-RC without initiating replication; this licensing is restricted to G1 by CDK activity that prevents re-licensing after S phase onset.^[22]^[23] In human cells, MCM proteins assemble specifically at ORC-bound sites during G1 before dispersing in S phase.^[22] Cells also monitor and maintain structural integrity in G1 by ensuring complete disassembly of mitotic spindle remnants from the prior division, with any persistent remnants repaired or cleared to avoid interference with the next cycle. In eukaryotes, incomplete spindle disassembly generates persistent microtubule-based remnants that inhibit bipolar spindle formation in the subsequent mitosis, necessitating active breakdown processes involving kinesins and microtubule-depolymerizing factors to restore cellular architecture.^[24] This clearance allows for repair of minor cytoskeletal damage accumulated during mitosis.^[25] In mammalian cells, histone synthesis begins to ramp up in late G1 as part of preparation for chromatin assembly following DNA replication in S phase. Cyclin E/CDK2 activity in late G1 activates transcription of replication-dependent histone genes, increasing histone mRNA and protein levels to provide the necessary supply for nucleosome assembly on newly synthesized DNA, with core histones like H3.1 entering the nucleus at the G1/S boundary.^[26]^[27] This coordinated upregulation ensures sufficient histones are available without excess, linking directly to the G1/S transition.^[28]

Molecular Regulation

Cyclins, CDKs, and Phosphorylation Cascades

The discovery of cyclins as key regulators of the cell cycle began in the early 1980s through studies on sea urchin embryos, where proteins were observed to accumulate and then undergo periodic degradation during early embryonic divisions.^[29] These findings laid the groundwork for identifying G1-specific cyclins in mammalian cells during the 1990s, using models such as fibroblasts and hematopoietic cells stimulated by growth factors.^[30] Cyclin D family members (D1, D2, and D3) were among the first characterized as G1 cyclins, with their expression induced in response to mitogenic signals to form active complexes with cyclin-dependent kinases (CDKs) 4 or 6.^[30] In early G1, the assembly of Cyclin D-CDK4/6 complexes initiates a phosphorylation cascade targeting the retinoblastoma protein (Rb), a central repressor of cell cycle progression.^[31] These complexes bind Rb and catalyze its initial phosphorylation at specific serine and threonine residues, partially inactivating Rb and leading to the partial release of bound E2F transcription factors, which then promote expression of genes required for S-phase entry.^[31] Full inactivation requires hyperphosphorylation, represented conceptually as:

\text{Rb} + p \rightarrow \text{hyperphosphorylated Rb (inactive)}

where p denotes phosphate groups added sequentially by CDKs, rendering Rb unable to repress E2F-dependent transcription of S-phase genes such as cyclin E and DNA replication factors.^[32] This step establishes the sequential nature of G1 regulation, with Cyclin D-CDK4/6 acting first to prime the system before downstream effectors take over. In mid-G1, Cyclin E accumulates and binds CDK2 to form an active complex that further hyperphosphorylates Rb, completing its inactivation and fully liberating E2F activity.^[33] The Cyclin E-CDK2 complex also contributes to replication licensing by phosphorylating pre-replication complex components, such as Cdc6, facilitating the loading of MCM helicases onto origins of replication in preparation for S phase. This sequential activation—Cyclin D first, followed by Cyclin E—ensures orderly progression through G1, with each complex building on the phosphorylation state established by the prior one.^[33] At the end of G1, both Cyclin D and Cyclin E levels decline through ubiquitin-mediated proteasomal degradation, resetting the cycle for the next round. Cyclin D is ubiquitinated by SCF^{FBX4-αB-crystallin} E3 ligase complexes after phosphorylation at Thr286, targeting it for 26S proteasome breakdown. Similarly, Cyclin E undergoes phosphorylation-dependent ubiquitination by SCF^{FBW7}, ensuring its timely removal to prevent premature S-phase entry. This degradation mechanism, conserved across eukaryotes, maintains precise temporal control of CDK activity during G1.^[34]

Growth Factor Signaling Pathways

Growth factors such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) initiate G1 phase entry by binding to receptor tyrosine kinases (RTKs), triggering dimerization, autophosphorylation, and recruitment of adaptor proteins like GRB2 and SOS.^[35] This activates the Ras-MAPK pathway, where Ras exchanges GDP for GTP, sequentially phosphorylating RAF, MEK, and ERK, leading to nuclear translocation of ERK and induction of transcription factors such as c-FOS and c-JUN that upregulate cyclin D1 expression.^[35] In turn, cyclin D1 promotes G1 progression by complexing with CDK4/6, as briefly noted in downstream regulation.^[35] The PI3K-Akt-mTOR pathway, activated concurrently by RTKs upon growth factor binding, provides essential metabolic support and enhances cell survival during G1.^[36] PIP3 produced by PI3K recruits Akt to the membrane, where PDK1 (phosphoinositide-dependent kinase 1) phosphorylates Akt at Thr308; activated Akt then inhibits TSC2 to activate mTORC1, promoting protein synthesis via S6K1 and 4E-BP1 phosphorylation, as well as lipid and nucleotide biosynthesis to meet biomass demands in G1.^[37] Additionally, mTORC2, formed via rictor transcription influenced by pathway feedback, phosphorylates Akt at Ser473 to suppress apoptosis and sustain viability.^[36] Cross-talk between growth factor pathways and JAK-STAT signaling integrates cytokine inputs, particularly in immune cells, to fine-tune G1 progression.^[38] For instance, STAT5 interacts with PI3K to upregulate Akt expression, amplifying survival signals from growth factors, while STAT3 is directly activated by EGFR to promote proliferation in lymphocytes and macrophages.^[38] In fibroblasts, serum starvation induces G0 arrest within 18 hours by depriving cells of growth factors, but re-addition of serum rescues entry into G1 and subsequent S phase within 20-24 hours.^[39] Pathway dominance varies by tissue; in skeletal muscle, insulin-like growth factors (IGFs) predominate, binding IGF-1R to activate PI3K-Akt and downregulate p27Kip1, facilitating G1/S transition in satellite cells for hypertrophy and repair.^[40]

Tumor Suppressors and Inhibitors

The retinoblastoma (Rb) family proteins, including pRb, p107, and p130, serve as central tumor suppressors in the G1 phase by maintaining a hypophosphorylated state that allows them to bind and repress E2F transcription factors.^[41] This binding recruits repressive chromatin-modifying complexes, such as histone deacetylases, to silence E2F target genes essential for S-phase entry, thereby preventing premature DNA replication and ensuring cellular fidelity.^[42] The activity of Rb proteins is preserved by inhibitors like p16^INK4a, which specifically binds CDK4/6-cyclin D complexes to block their phosphorylation of Rb, sustaining the repressive hypophosphorylated form and halting G1 progression.^[43] The p53 tumor suppressor pathway provides an additional layer of negative regulation, particularly in response to cellular stress, by transcriptionally activating p21^WAF1/CIP1, a potent CDK inhibitor.^[44] p21 binds to and inhibits cyclin E-CDK2 and other G1 CDKs, leading to G1 arrest and allowing time for damage repair or apoptosis induction.^[45] Mutations in p53, found in approximately 50% of human cancers, disrupt this inhibition, permitting unchecked G1-to-S transition and promoting tumorigenesis.^[46] Other key inhibitors include PTEN, a phosphatase that antagonizes PI3K by dephosphorylating PIP3 to PIP2, thereby suppressing Akt-mediated promotion of G1 progression and inducing p27^Kip1 expression to further inhibit CDK2 activity.^[47] Members of the CIP/KIP family, such as p27^Kip1 and p57^Kip2, act as versatile CDK binders that inhibit cyclin D-CDK4/6 and cyclin E-CDK2 complexes, enforcing G1 quiescence and functioning as tumor suppressors by limiting proliferative signals.^[48] Feedback loops involving E2F contribute to robust negative regulation, with E2F activators undergoing auto-regulation where their induced targets, like cyclin A, trigger CDK2-mediated phosphorylation and subsequent ubiquitin-dependent degradation of E2F proteins, dampening S-phase gene expression at the end of G1.^[49] These mechanisms collectively ensure that G1 exit occurs only under appropriate conditions, integrating with checkpoint surveillance to maintain genomic stability.^[42]

Key Transitions and Checkpoints

Restriction Point

The restriction point (R point) represents the stage in mid-to-late G1 phase where mammalian cells irreversibly commit to completing the cell cycle, becoming independent of external mitogenic signals for progression into S phase.^[50] This commitment occurs approximately 2-3 hours before the onset of DNA replication in typical mammalian cells, marking a critical transition beyond which cells will proceed to division even if growth factors are withdrawn.^[51] In yeast, an analogous event known as "Start" serves a similar function, committing cells to the cell cycle in response to nutrient availability, though the upstream signals differ between species.^[52] At the molecular level, passage through the restriction point is driven by the accumulation of active cyclin E-CDK2 complexes, which hyperphosphorylate the retinoblastoma protein (Rb), leading to its inactivation and the release of E2F transcription factors.^[53] This process creates a bistable switch mechanism, where initial Rb phosphorylation by cyclin D-CDK4/6 primes the system, but cyclin E-CDK2 activity establishes a positive feedback loop that ensures robust, irreversible commitment by amplifying E2F-driven expression of S-phase genes, including cyclin E itself. The threshold of CDK2 activity required for this switch is precise, integrating cumulative mitogen signaling to prevent premature or stochastic entry into the cell cycle. The concept of the restriction point was first experimentally defined in the 1970s through studies on non-transformed mammalian fibroblasts, where Arthur Pardee demonstrated that cells deprived of serum (and thus mitogens) after a specific point in G1 continued to enter S phase and divide, whereas earlier withdrawal induced quiescence. These seminal experiments, using synchronized cell populations and isotopic labeling to track DNA synthesis, established the R point as a discrete, mitogen-independent commitment step approximately midway through G1.^[54] Debates persist regarding the exact molecular identity of the restriction point, with some studies proposing it as a singular event dominated by cyclin E-CDK2 activity and Rb hyperphosphorylation, while others suggest multiple sub-thresholds involving E2F accumulation or additional CDK targets.^[55] For instance, evidence indicates that E2F threshold levels may contribute independently of full CDK dominance in certain contexts, challenging a purely CDK-centric model. Recent single-cell analyses from the 2020s support hybrid models that reconcile these views, showing variability in commitment timing influenced by cell history, size, and stochastic fluctuations in CDK and E2F dynamics across individual cells.^[56]

G1/S Checkpoint

The G1/S checkpoint serves as a critical surveillance mechanism at the G1/S boundary, detecting DNA damage or replication stress to prevent the initiation of DNA synthesis in compromised cells. This checkpoint ensures genomic integrity by halting cell cycle progression, allowing time for damage assessment and repair, and it operates primarily through the activation of DNA damage response (DDR) pathways.^[57] Activation of the G1/S checkpoint begins when ATM (ataxia-telangiectasia mutated) and ATR (ATM- and Rad3-related) kinases sense DNA lesions, such as double-strand breaks or replication fork stalling.^[58] ATM primarily responds to double-strand breaks by autophosphorylating and activating downstream effectors, while ATR is triggered by single-stranded DNA exposed during replication stress.^[59] These kinases phosphorylate p53, a tumor suppressor transcription factor, stabilizing it and enhancing its activity to upregulate p21 (CDKN1A), a cyclin-dependent kinase inhibitor.^[57] Elevated p21 levels then bind and inhibit cyclin E-CDK2 complexes, preventing phosphorylation of Rb and subsequent release of E2F transcription factors required for S-phase entry.^[60] The signaling cascade involves checkpoint kinases Chk1 and Chk2, which mediate the response: Chk2 is phosphorylated by ATM and amplifies p53 activation, while Chk1 is targeted by ATR to enforce replication stress signaling.^[58] This pathway can be summarized as: DNA damage → ATM/ATR activation → Chk1/Chk2 phosphorylation → p53 stabilization → p21 transcription → CDK inhibition and G1 arrest.^[61] The Rb pathway contributes to this inhibition by maintaining E2F repression, as detailed in the tumor suppressors section. Upon activation, the G1/S checkpoint induces a temporary cell cycle arrest to facilitate DNA repair via mechanisms like non-homologous end joining or base excision repair; if damage is irreparable, it triggers apoptosis through sustained p53 activity. Unlike the G2/M checkpoint, where chromosomes condense during mitosis complicating repair access, the G1/S arrest occurs in decondensed chromatin, enabling more efficient and complete lesion resolution.^[62] The G1/S checkpoint represents the primary decision point for replication fidelity, integrating damage signals to avert mutagenesis, though it is notably absent in rapidly dividing embryonic cells, which lack a defined G1 phase and rely on alternative safeguards.^[63]

Pathological and Physiological Roles

Implications in Cancer

Deregulation of the G1 phase is a hallmark of cancer, primarily through alterations in key regulators that promote uncontrolled cell proliferation. Loss of the retinoblastoma (Rb) tumor suppressor protein is a frequent event, occurring in nearly all cases of retinoblastoma and in approximately 90-100% of small cell lung cancers (SCLC), where it facilitates bypass of the G1/S checkpoint.^[64] Amplification of cyclin D1 (CCND1) is observed in 10-35% of breast cancers, particularly in hormone receptor-positive subtypes, leading to hyperactivation of CDK4/6 and premature progression through G1.^[65] Deletion of the p16^INK4a^ gene (CDKN2A), an inhibitor of CDK4/6, is common across various malignancies, including in 10-40% of gastric cancers (often via homozygous deletion) and frequent homozygous deletions in glioblastomas, resulting in unchecked cyclin D-CDK activity.^[66]^[67] These alterations shorten the G1 phase, enabling rapid cell cycling and accumulation of genomic instability that drives oncogenesis. For instance, Rb loss disrupts E2F repression, allowing constitutive expression of S-phase genes and evasion of growth arrest signals. In viral oncogenesis, high-risk human papillomavirus (HPV) type 16 E7 protein binds and inactivates Rb, promoting cell cycle entry and contributing to cervical cancer development by destabilizing the Rb-E2F complex.^[68] Therapeutically, targeting G1 regulators has shown promise, particularly with CDK4/6 inhibitors that restore cell cycle control. Palbociclib, the first-in-class CDK4/6 inhibitor, was approved by the FDA in 2015 for combination with letrozole in hormone receptor-positive (HR+), HER2-negative advanced breast cancer, inducing G1 arrest and improving progression-free survival. These inhibitors have since expanded to the adjuvant setting for early-stage disease: abemaciclib was approved in 2021 (with expansion in 2023) and ribociclib in 2024 for high-risk HR+, HER2- early breast cancer, with 2025 trial data (e.g., from monarchE and NATALEE) confirming long-term improvements in invasive disease-free survival.^[69]^[70]^[71]^[72] As of 2025, clinical trials continue to explore combinations of CDK4/6 inhibitors with PD-1 blockade across cancers such as breast and head/neck squamous cell carcinoma, demonstrating synergistic antitumor effects by enhancing T-cell infiltration and reducing regulatory T cells, though with noted hepatotoxicity risks.^[73]^[74] Diagnostically, G1 phase markers assessed via flow cytometry provide insights into tumor aggressiveness. Lower G0/G1-phase fractions correlate with high-grade tumors, such as gliomas, where reduced G1 duration indicates aggressive proliferation and aids in grading and prognosis.^[75]

Role in Quiescence and Differentiation

The G1 phase plays a pivotal role in transitioning cells into quiescence (G0), a reversible state of cell cycle withdrawal triggered by extrinsic cues such as nutrient deprivation or contact inhibition. Under nutrient limitation, cells exit the proliferative cycle during G1, maintaining hypophosphorylated retinoblastoma protein (Rb), which represses E2F transcription factors and halts expression of genes required for S phase entry.^[76] Similarly, contact inhibition in confluent cultures induces G1 arrest through Rb-E2F-mediated repression, preventing unnecessary proliferation in dense tissues.^[77] In hepatocytes, for instance, serum or amino acid deprivation prompts entry into G0, where cells preserve metabolic functions and viability while suspending growth, allowing rapid regeneration upon nutrient replenishment.^[78] In developmental contexts, an extended G1 phase in stem and progenitor cells facilitates lineage commitment and differentiation by providing temporal windows for fate-determining signals. Prolonged G1 duration correlates with upregulation of cyclin-dependent kinase inhibitor p27^Kip1, which reinforces Rb hypophosphorylation and suppresses proliferation-promoting genes.^[79] For example, in neural progenitors, p27^Kip1 accumulation during late G1 promotes exit from the cell cycle, enabling differentiation into post-mitotic neurons and radial migration in the cerebral cortex.^[80] This mechanism ensures that asymmetric divisions in stem cell niches balance self-renewal with differentiation, as seen in embryonic and adult neurogenesis.^[81] Senescence represents an irreversible G1 arrest, distinct from quiescence, induced by persistent stresses like oncogene activation, replicative exhaustion in aging, or therapeutic interventions. Activation of the p16^INK4a-Rb pathway inhibits CDK4/6, sustaining Rb's repressive function on E2F targets, while p53-p21 signaling reinforces the arrest by blocking CDK2 activity.^[82] This dual mechanism was notably elucidated in studies of oncogene-induced senescence during the 2000s and therapy-induced senescence in the 2010s, highlighting G1 as the primary checkpoint for eliminating damaged cells.^[83] Re-entry from quiescence back into G1 is orchestrated by mitogenic stimuli, such as growth factors, which rapidly induce cyclin D expression and assembly with CDK4/6 complexes. This initiates partial Rb phosphorylation, gradually releasing E2F repression and reactivating the cell cycle machinery without immediate S phase commitment.^[84] In quiescent fibroblasts or hepatocytes, this process restores proliferative competence, underscoring G1's flexibility in responding to environmental cues.^[85]

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The PI3K-Akt-mTOR and Wnt pathways converge and regulate the progression of cell cycle through G0-G1-S-phases and reprogram the metabolism in cancer cells.
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Mitogenic signals that stimulate cell progress through G1 increase the expression of cyclin D isoforms in early G1, which form complexes with CDK4 and/or CDK6.