GO:1902807 negative regulation of cell cycle G1/S phase transition: Cell Cycle Checkpoint Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902807 describes any signaling pathway that decreases or inhibits cyclin-dependent protein kinase activity to block the switch from G1 phase to S phase.
• The G1/S transition is controlled by the balance between cyclin E/CDK2 activation and the abundance of the CDK inhibitor p27Kip1, which is degraded by proteolysis to permit S phase entry.
• Negative regulators of G1/S include CDK inhibitors such as p27Kip1 and the ubiquitin-proteasome machinery that controls cyclin E turnover.
• E2F1 and its cofactors, including Api5 and Ror2, coordinate transcriptional programs that either promote or restrain G1/S progression.
• Dysregulation of G1/S negative regulation is a hallmark of cancer, where loss of checkpoint control drives uncontrolled proliferation.
• CRISPR knockout, point mutation, knock-in and overexpression models allow causal testing of candidate negative regulators of G1/S in disease-relevant cell types.
Description
The transition from G1 phase to S phase is a decisive checkpoint in the eukaryotic cell cycle, committing a cell to DNA replication and division. GO:1902807, negative regulation of cell cycle G1/S phase transition, captures the signaling pathways that decrease or inhibit the activity of cyclin-dependent protein kinases (CDKs) to prevent this commitment. This regulatory process is essential for maintaining genomic integrity, coordinating cell growth with division, and preventing unscheduled proliferation that can lead to cancer. Researchers study GO:1902807 to understand how cells pause or arrest the cell cycle in response to developmental cues, DNA damage, or therapeutic intervention. The process is conserved from yeast to humans, with core mechanisms involving CDK inhibitors, ubiquitin-mediated proteolysis of cyclins, and transcriptional control by E2F family proteins. In yeast, tumor suppressor-like proteins and checkpoint regulators govern G1/S transition, providing a genetically tractable model for dissecting negative regulation. In mammalian cells, serum growth factors and extracellular signals modulate G1 phase transit, and withdrawal of such signals leads to G1 arrest through negative regulatory pathways. The clinical relevance of GO:1902807 is underscored by its frequent disruption in human malignancies, where loss of negative regulation at G1/S contributes to uncontrolled cell proliferation. Understanding the molecular players and mechanisms of this process is therefore critical for identifying therapeutic targets and biomarkers.
negative regulation of cell cycle G1/S phase transition At A Glance
| GO ID | GO:1902807 |
|---|---|
| GO term | negative regulation of cell cycle G1/S phase transition |
| Ontology | biological_process |
| Synonym | down regulation of cell cycle G1/S phase transition; down-regulation of cell cycle G1/S phase transition; downregulation of cell cycle G1/S phase transition; inhibition of cell cycle G1/S phase transition |
| Major function | Inhibits cyclin-dependent protein kinase activity to block the G1 to S phase switch |
| Related processes | Cell cycle arrest, DNA damage response, cell cycle checkpoint control |
| Key regulators | CDK inhibitors (e.g., p27Kip1), E2F1, ubiquitin-proteasome components |
| Disease relevance | Cancer, proliferative disorders, developmental abnormalities |
What Is GO:1902807?
GO:1902807 is a biological process term defined as any signaling pathway that decreases or inhibits the activity of a cell cycle cyclin-dependent protein kinase to modulate the switch from G1 phase to S phase of the cell cycle. In simpler terms, it encompasses all mechanisms that put the brakes on the G1-to-S transition, preventing cells from prematurely or inappropriately entering DNA synthesis. This includes pathways that reduce CDK activity through direct inhibition, degradation of cyclins, or transcriptional repression of S-phase genes.
Why Is negative regulation of cell cycle G1/S phase transition Important in Cell Biology?
Negative regulation of the G1/S transition is a fundamental safeguard against unscheduled cell division. It ensures that cells only replicate their DNA when conditions are favorable and that damaged cells arrest before committing to S phase. Loss of this regulation is a common event in cancer, where overexpression of cyclins or loss of CDK inhibitors drives proliferation. Moreover, this process is a target of many anticancer therapies that aim to restore cell cycle checkpoints. Studying GO:1902807 helps researchers identify new therapeutic targets and understand mechanisms of drug resistance.
• Prevents premature entry into S phase, maintaining genomic stability.
• Controls cell proliferation in response to growth signals and stress.
• Dysregulation leads to cancer, including triple-negative breast cancer.
• Involved in developmental processes and tissue homeostasis.
• Provides targets for CDK inhibitors used in cancer therapy.
• Conserved from yeast to humans, enabling model organism studies.
• Modulates cell cycle in non-mammalian species such as oysters.
• Key for understanding cell cycle checkpoints and DNA damage responses.
What Happens During negative regulation of cell cycle G1/S phase transition?
Inhibition of Cyclin-Dependent Kinase Activity
In simple terms: This step puts the brakes on the enzymes that drive the cell cycle forward.
Negative regulation of G1/S transition primarily targets cyclin-dependent kinases (CDKs) such as CDK2, which partners with cyclin E to phosphorylate retinoblastoma protein (Rb) and initiate S phase. CDK inhibitors like p27Kip1 bind to and inhibit cyclin E/CDK2 complexes, preventing Rb phosphorylation and blocking G1/S progression. The abundance of p27Kip1 is controlled by ubiquitin-mediated proteolysis, and its degradation is required for cells to enter S phase.
Proteolysis of Cyclin E and p27Kip1
In simple terms: Cells destroy key cell cycle proteins to stop division.
The ubiquitin-proteasome system degrades both cyclin E and p27Kip1, but negative regulation can occur when degradation of p27Kip1 is blocked or when cyclin E is prematurely degraded. Nakayama et al. demonstrated that proteolysis of cyclin E and p27Kip1 is critical for regulating the G1-S transition, with p27Kip1 degradation required for S phase entry. Conversely, factors that promote p27Kip1 stability or inhibit its degradation enforce negative regulation.
Transcriptional Control by E2F1 and Cofactors
In simple terms: Gene expression programs can either promote or block the transition.
E2F1 is a transcription factor that controls genes required for S phase, but its activity is modulated by cofactors. Api5 contributes to E2F1 control of the G1/S phase transition, and its depletion can alter cell cycle progression. Similarly, E2F1-Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S transition in fibroblasts, indicating that negative regulation can occur through interference with such positive feedback loops.
Extracellular Signals and Serum Dependence
In simple terms: Cells need external growth signals to pass the checkpoint; without them, they stop.
Serum growth factors are required for G1 phase transit in NIH-3T3 cells, and serum withdrawal leads to G1 arrest through negative regulatory pathways. This highlights how extracellular cues are integrated into the cell cycle machinery to inhibit CDK activity and prevent S phase entry when conditions are unfavorable.
Conservation in Yeast and Invertebrates
In simple terms: The same braking mechanisms exist in simple organisms.
In yeast, tumor suppressor-like proteins regulate the G1/S transition, providing insights into conserved negative regulatory mechanisms. In oysters, an ATP-binding cassette transporter G2 (CgABCG2) regulates haemocyte proliferation by modulating the G1/S phase transition, showing that negative regulation extends to invertebrate immunity.
Key Genes Involved in GO:1902807 negative regulation of cell cycle G1/S phase transition
The following genes and proteins are central to the negative regulation of the G1/S phase transition, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CDKN1B (p27Kip1) | CDK inhibitor that binds and inhibits cyclin E/CDK2 | Its degradation is required for G1/S transition; stability enforces negative regulation |
| CCNE1 (Cyclin E) | Activator of CDK2; its proteolysis regulates G1/S | Proteolysis of cyclin E is critical for G1-S control |
| E2F1 | Transcription factor controlling S-phase genes | Its activity is modulated by cofactors like Api5 and Ror2 |
| API5 | Apoptosis inhibitor that contributes to E2F1 control | Modulates E2F1-mediated G1/S transition |
| ROR2 | Receptor tyrosine kinase mediating E2F1 signaling | E2F1-Ror2 signaling promotes G1/S transition in fibroblasts |
| IGF2BP2 | m6A reader that promotes CDK6 translation | Drives cell cycle progression in triple-negative breast cancer |
| CDK6 | Cyclin-dependent kinase that promotes G1/S | Its translation is enhanced by IGF2BP2 in cancer |
| FSCN1 (Fascin) | Actin-bundling protein | Modulates cell cycle checkpoint regulators of G1-S in breast cancer |
| CgABCG2 | ABC transporter in oyster | Regulates haemocyte proliferation via G1/S modulation |
| p27Kip1 | CDK inhibitor | Key negative regulator; proteolysis controls G1/S |
| Cyclin E | CDK2 partner | Degradation regulates G1/S transition |
| EIF4A1 | Translation initiation factor | Recruited by IGF2BP2 to promote CDK6 translation |
| Rb | Retinoblastoma protein | Phosphorylated by CDK2 to release E2F; negative regulation prevents phosphorylation |
| CDK2 | Cyclin-dependent kinase | Target of inhibition by p27Kip1 |
| Skp2 | F-box protein that degrades p27Kip1 | Promotes G1/S by degrading p27Kip1 |
| Cdh1 | APC/C activator | Degrades cyclin E and other mitotic regulators |
How Is negative regulation of cell cycle G1/S phase transition Regulated?
The negative regulation of G1/S transition is itself regulated by multiple upstream signals. Growth factor signaling through pathways such as PI3K/AKT can promote G1/S by inactivating CDK inhibitors, while stress signals activate checkpoints that enforce arrest. The ubiquitin-proteasome system dynamically controls the levels of cyclin E and p27Kip1, with Skp2 and Cdh1 playing opposing roles. Transcriptional regulation by E2F1 and its cofactors, such as Api5 and Ror2, adds another layer of control. In cancer, oncogenic signals like IGF2BP2 can override negative regulation by enhancing CDK6 translation. Extracellular cues, including serum factors, are required for G1 transit, and their withdrawal leads to arrest.
negative regulation of cell cycle G1/S phase transition and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CDKN1B (p27Kip1) | Cancer, multiple endocrine neoplasia | Knockout and point mutation in cancer cell lines |
| CCNE1 | Breast cancer, ovarian cancer | Overexpression and knockout in MCF-7 cells |
| IGF2BP2 | Triple-negative breast cancer | Knockdown and overexpression in TNBC cell lines |
| FSCN1 | Breast cancer | Knockout in MDA-MB-231 cells |
| E2F1 | Cancer, developmental disorders | Knock-in of mutant E2F1 in fibroblasts |
Cancer
Dysregulation of G1/S negative regulation is a hallmark of cancer. Loss of p27Kip1 or overexpression of cyclin E and CDK6 drives uncontrolled proliferation. In triple-negative breast cancer, IGF2BP2 promotes CDK6 translation, accelerating cell cycle progression. Fascin modulates G1-S checkpoint regulators in breast cancer cells, contributing to proliferation. Targeting these pathways is a therapeutic strategy.
Developmental Disorders
Proper negative regulation of G1/S is essential for normal development. Disruption of E2F1 control by Api5 can affect cell cycle exit and differentiation. E2F1-Ror2 signaling is important for fibroblast proliferation in response to bFGF, and its dysregulation may contribute to developmental abnormalities.
Infectious and Immune Responses
In oysters, CgABCG2 regulates haemocyte proliferation by modulating G1/S transition, linking cell cycle control to immune responses. This suggests that negative regulation of G1/S may play roles in host defense and inflammation across species.
From negative regulation of cell cycle G1/S phase transition-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of p27Kip1 accelerate G1/S transition? | CDKN1B knockout cell line |
| Does a point mutation in cyclin E affect CDK2 binding? | CCNE1 point-mutation knock-in |
| Can overexpression of IGF2BP2 drive proliferation? | IGF2BP2 overexpression in TNBC cells |
| Does tagging E2F1 reveal its interaction partners? | E2F1 tagged knock-in |
| Does knockout of Fascin alter G1/S checkpoint regulators? | FSCN1 knockout in breast cancer cells |
| Does CgABCG2 regulate haemocyte proliferation? | CgABCG2 knockout in oyster cells |
How to Study the negative regulation of cell cycle G1/S phase transition Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Flow cytometry | DNA content and cell cycle distribution | Assessing G1 arrest after gene knockout |
| Western blot | Protein expression and degradation | Measuring p27Kip1 and cyclin E levels |
| RNA-seq | Transcriptional changes | Identifying E2F1 target genes |
| CRISPR screen | Gene essentiality and proliferation | Discovering novel G1/S regulators |
| Proteomics | Protein interactions and modifications | Mapping ubiquitination of cyclin E |
| Immunofluorescence | Subcellular localization | Visualizing CDK inhibitors in nucleus |
| qPCR | mRNA levels | Validating gene expression changes |
Flow Cytometry
Flow cytometry measures DNA content to assess cell cycle distribution, allowing quantification of G1, S, and G2/M populations. It is widely used to evaluate the effects of negative regulators on G1/S transition.
Western Blotting
Western blotting detects protein levels of cyclins, CDKs, and CDK inhibitors such as p27Kip1 and cyclin E, providing insights into proteolysis and expression changes.
RNA Sequencing
RNA-seq profiles global gene expression changes upon modulation of negative regulators, revealing transcriptional programs controlled by E2F1 and other factors.
CRISPR Screening
Genome-wide CRISPR screens identify genes that, when knocked out, alter G1/S transition, uncovering novel negative regulators.
How CRISPR Can Be Used to Study GO:1902807 negative regulation of cell cycle G1/S phase transition
Knockout
CRISPR knockout of negative regulators such as CDKN1B (p27Kip1) can accelerate G1/S transition and increase proliferation, providing causal evidence for their role. Knockout of E2F1 cofactors like API5 can also alter cell cycle progression.
Point Mutation
Point mutations in cyclin E or CDK2 can disrupt binding to inhibitors, leading to constitutive activation. CRISPR point mutation models help dissect specific residues required for negative regulation.
Knock-in
Knock-in of tagged versions of E2F1 or p27Kip1 allows tracking of protein dynamics and interactions in live cells, revealing how negative regulation is orchestrated.
Overexpression
Overexpression of negative regulators like p27Kip1 or API5 can induce G1 arrest or alter cell cycle kinetics, validating their function in disease models.
How EDITGENE Supports negative regulation of cell cycle G1/S phase transition Research
Researchers studying negative regulation of cell cycle G1/S phase transition-related genes often need to determine whether a candidate gene is causally involved in the process or merely correlated with changes in proliferation. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such causal studies in relevant cell models.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cell cycle G1/S phase transition research.
Frequently Asked Questions About negative regulation of cell cycle G1/S phase transition
What is negative regulation of cell cycle G1/S phase transition?
It is a biological process (GO:1902807) that inhibits cyclin-dependent kinase activity to block the transition from G1 to S phase, preventing DNA replication.
What genes are involved in negative regulation of cell cycle G1/S phase transition?
Key genes include CDKN1B (p27Kip1), CCNE1 (cyclin E), E2F1, API5, ROR2, and IGF2BP2, among others.
How does p27Kip1 regulate the G1/S transition?
p27Kip1 binds and inhibits cyclin E/CDK2 complexes; its degradation by the ubiquitin-proteasome system is required for S phase entry.
What diseases are associated with dysregulation of G1/S negative regulation?
Cancer, particularly breast cancer, and developmental disorders are linked to loss of negative regulation at G1/S.
What methods are used to study negative regulation of G1/S transition?
Flow cytometry, western blotting, RNA-seq, and CRISPR screens are commonly used.
How can CRISPR be used to study G1/S negative regulation?
CRISPR knockout, point mutation, knock-in, and overexpression models allow causal testing of candidate genes.
What is the role of E2F1 in G1/S transition?
E2F1 is a transcription factor that controls S-phase genes; its activity is modulated by cofactors like Api5 and Ror2.
Is negative regulation of G1/S conserved across species?
Yes, it is conserved from yeast to humans, with similar mechanisms involving CDK inhibitors and proteolysis.
What is the GO ID for negative regulation of cell cycle G1/S phase transition?
The GO ID is GO:1902807.
How does serum affect G1/S transition?
Serum growth factors are required for G1 phase transit; serum withdrawal leads to G1 arrest through negative regulatory pathways.
Conclusion
Negative regulation of the cell cycle G1/S phase transition (GO:1902807) is a critical process that safeguards against unscheduled DNA replication. Its molecular players, including CDK inhibitors, E2F1 cofactors, and ubiquitin-proteasome components, are frequently dysregulated in cancer and other diseases. Understanding these mechanisms offers opportunities for therapeutic intervention. EDITGENE provides advanced CRISPR tools to dissect this process and identify novel targets.
References
- 1. Nakayama KI et al.. 2001. Regulation of the cell cycle at the G1-S transition by proteolysis of cyclin E and p27Kip1.. Biochem Biophys Res Commun 282(4):853-60 PMID: 11352628
- 2. Yu S et al.. 2023. An ATP-binding cassette transporter G2 (CgABCG2) regulates the haemocyte proliferation by modulating the G1/S phase transition of cell cycle in oyster Crassostrea gigas.. Fish Shellfish Immunol 136:108441 PMID: 36403705
- 3. Xia T et al.. 2024. IGF2BP2 Drives Cell Cycle Progression in Triple-Negative Breast Cancer by Recruiting EIF4A1 to Promote the m6A-Modified CDK6 Translation Initiation Process.. Adv Sci (Weinh) 11(1):e2305142 PMID: 37983610
- 4. Garcia-Jove Navarro M et al.. 2013. Api5 contributes to E2F1 control of the G1/S cell cycle phase transition.. PLoS One 8(8):e71443 PMID: 23940755
- 5. Li P et al.. 2021. Tumor suppressor stars in yeast G1/S transition.. Curr Genet 67(2):207-212 PMID: 33175222
- 6. Ghebeh H et al.. 2025. Fascin Drives Breast Cancer Cell Proliferation Partly by Modulating the Cell Cycle Checkpoint Regulators of the G1-S Phase.. Cells 14(23) PMID: 41369328
- 7. DiSalvo CV et al.. 1995. Regulation of NIH-3T3 cell G1 phase transit by serum during exponential growth.. Cell Prolif 28(9):511-24 PMID: 7578600
- 8. Endo M et al.. 2020. E2F1-Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S phase transition in bFGF-stimulated NIH/3T3 fibroblasts.. FASEB J 34(2):3413-3428 PMID: 31922321
