G1

G1
Name	G1
Field	Cell biology
Key figures	Paul Nurse, Leland H. Hartwell, Tim Hunt, Andrew W. Murray
Related terms	S phase, G2 phase, M phase, G0 phase, Restriction point, Cyclin-dependent kinase, Retinoblastoma protein

G1 G1 is the first gap phase in the eukaryotic cell cycle, occupying the interval between mitosis and DNA synthesis. It is a period of cell growth, biosynthetic activity, and preparation for commitment to replication, where cells integrate signals from pathways such as those mediated by Epidermal growth factor, Transforming growth factor beta, p53, and Retinoblastoma protein to decide whether to enter S phase. G1 has been studied across model organisms including Saccharomyces cerevisiae, Schizosaccharomyces pombe, Xenopus laevis, Drosophila melanogaster, Mus musculus, and Homo sapiens and is central to research on cancer, development, and aging.

Definition and overview

G1 is defined as the post-mitotic, pre-replicative interval of the canonical eukaryotic cell cycle composed of G1 phase, S phase, G2 phase, and M phase. In many metazoans the duration of G1 is variable and responsive to extracellular cues such as Insulin-like growth factor 1, Platelet-derived growth factor, and Fibroblast growth factor. Canonical regulators include members of the Cyclin D and Cyclin E families, Cyclin-dependent kinase 4, Cyclin-dependent kinase 6, and Cyclin-dependent kinase 2. Classical genetic screens in Saccharomyces cerevisiae by Leland H. Hartwell and molecular studies by Paul Nurse and Tim Hunt identified cyclins and cyclin-dependent kinases as pivotal for the timing and control of G1 progression.

G1 phase in the cell cycle

During G1 cells increase mass, synthesize RNA and protein, and prepare organelles for duplication; in embryonic cell cycles of Drosophila melanogaster and Xenopus laevis early embryos G1 is shortened or absent. The restriction point concept, characterized in mammalian cells by work linked to Arthur Pardee, marks an irreversible commitment late in G1 after which cells progress to S phase independent of mitogens. Checkpoints monitor DNA damage via pathways involving ATM, ATR, and p53, while metabolic checkpoints integrate signals from AMP-activated protein kinase, mTOR, and MYC to couple nutrient status to G1 progression. In unicellular models such as Saccharomyces cerevisiae G1 length correlates with cell size and mating pheromone responses mediated by FAR1 and STE pathway components.

Molecular regulation and checkpoints

Molecular control in G1 centers on the sequential activation and inactivation of cyclin–CDK complexes and pocket proteins; Cyclin D–CDK4/CDK6 initiate phosphorylation of Retinoblastoma protein family members, releasing E2F transcription factor family proteins to activate genes required for S phase entry. Inhibitors such as p21 (CDKN1A), p27 (CDKN1B), and INK4 proteins antagonize CDK activity. DNA damage triggers stabilization of p53, inducing transcription of p21 and engaging the G1 DNA damage checkpoint, while persistent damage can lead to senescence mediated by p16 (CDKN2A), RB1, and components of the senescence-associated secretory phenotype. Replication licensing factors such as CDC6, MCM proteins, and ORC (origin recognition complex) are regulated during G1 to prevent re-replication, coordinated by ubiquitin ligases like SCF complex and APC/C.

Variations and related states (G0, G1/S transition)

Cells can exit G1 into a quiescent state termed G0 phase, as seen in differentiated cells of Homo sapiens tissues such as hepatocytes and neurons; re-entry from G0 requires mitogenic stimulation and reactivation of Cyclin D expression. The G1/S transition is orchestrated by a rise in Cyclin E–CDK2 activity and completion of the restriction point; oncogenic lesions in TP53, RB1, CDKN2A, CCND1 (Cyclin D1), or amplification of CDK4 can deregulate this transition and drive uncontrolled proliferation. Developmental regulation examples include cell cycle remodeling during Drosophila melanogaster embryogenesis and G1 lengthening during differentiation of Mus musculus neural progenitors.

Biological significance and implications in disease

Aberrant control of G1 contributes to oncogenesis; common alterations include loss of RB1 function, mutation of TP53, amplification of CCND1, and deletion of CDKN2A, which are recurrent in cancers such as breast cancer, lung cancer, colorectal cancer, and glioblastoma. G1 dysfunction also underlies aspects of aging and degenerative disease through accumulation of senescent cells driven by p16INK4a and chronic NF-κB–mediated inflammation. Therapeutic strategies targeting G1 regulators include palbociclib and other CDK4/6 inhibitors approved for breast cancer and under investigation in combinations with inhibitors of PI3K, mTOR, MEK, and immune checkpoint blockers like pembrolizumab.

Experimental methods and measurement approaches

G1 is assayed by flow cytometry of DNA content using propidium iodide or DAPI staining combined with markers such as Ki-67 and 5-ethynyl-2'-deoxyuridine (EdU) incorporation to distinguish G0/G1 from S-phase cells. Live-cell imaging with fluorescent reporters like the FUCCI system (fluorescent ubiquitination-based cell cycle indicator) and biosensors for cyclin-dependent kinase activity enable dynamic measurement in HeLa cells, NIH 3T3 cells, and primary human fibroblasts. Genetic perturbation using CRISPR-Cas9, RNA interference with siRNA or shRNA, and chemical inhibition with compounds targeting CDK2 or CDK4/6 are standard approaches to probe G1 control, complemented by chromatin immunoprecipitation assays for E2F targets and transcriptomic profiling via RNA-seq.

Category:Cell cycle