GO:1902806 regulation of cell cycle G1/S phase transition: Signaling Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902806 describes any signaling pathway that modulates cyclin-dependent protein kinase activity to control the switch from G1 phase to S phase of the cell cycle.
• The G1/S transition is a point of no return where cells commit to DNA replication, and its dysregulation is a hallmark of cancer and other proliferative disorders.
• Cyclin D-CDK4/6, cyclin E-CDK2, and the RB-E2F axis are central regulators of this transition, integrating growth signals and checkpoint controls.
• Accurate measurement of G1/S progression in living cells is now possible with reporters such as PIP-FUCCI, enabling dynamic studies of phase transitions.
• Non-coding RNAs and micropeptides, such as LINC00998-encoded SMIM30, can modulate the G1/S transition by regulating cytosolic calcium levels.
• Diverse model systems, from mammalian cells to oyster haemocytes, reveal conserved and species-specific mechanisms of G1/S regulation.
Description
The transition from G1 phase to S phase is a critical decision point in the cell cycle, where cells commit to DNA replication and division. GO:1902806, regulation of cell cycle G1/S phase transition, encompasses the signaling pathways that modulate the activity of cyclin-dependent protein kinases (CDKs) to control this switch. This process ensures that cells integrate growth signals, nutrient availability, and stress cues before initiating DNA synthesis, thereby maintaining genomic integrity. Researchers study this term to understand how normal proliferation is controlled and how its dysregulation contributes to diseases such as cancer. The G1/S transition is orchestrated by a network of cyclins, CDKs, and checkpoint proteins, with the retinoblastoma (RB) protein and E2F transcription factors serving as key effectors. Recent advances in live-cell imaging, such as the PIP-FUCCI reporter, allow precise delineation of G1/S phase transitions in individual cells, facilitating dynamic studies of regulatory mechanisms. Moreover, emerging evidence highlights the role of non-coding RNAs and micropeptides in modulating this transition, expanding the scope of regulatory inputs. Understanding GO:1902806 is therefore essential for both basic cell biology and translational research targeting proliferative diseases.
regulation of cell cycle G1/S phase transition At A Glance
| GO ID | GO:1902806 |
|---|---|
| GO term | regulation of cell cycle G1/S phase transition |
| Ontology | biological_process |
| Synonym | none |
| Major function | Modulation of cyclin-dependent protein kinase activity to control the G1 to S phase switch |
| Key regulators | Cyclin D-CDK4/6, cyclin E-CDK2, RB, E2F, CDK inhibitors (p21, p27) |
| Associated diseases | Cancer, proliferative disorders |
| Research methods | Live-cell imaging (PIP-FUCCI), flow cytometry, CRISPR screens, RNA-seq |
What Is GO:1902806?
GO:1902806, regulation of cell cycle G1/S phase transition, is defined as any signaling pathway that modulates 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 other words, it includes all molecular events that either promote or inhibit the commitment of a cell to enter S phase by acting on CDK complexes and their regulators.
Why Is regulation of cell cycle G1/S phase transition Important in Cell Biology?
The regulation of the G1/S phase transition is fundamental to cell proliferation and tissue homeostasis. Dysregulation of this process leads to uncontrolled cell division, a hallmark of cancer, and is also implicated in developmental disorders and degenerative diseases. Understanding the signaling pathways that control CDK activity at this checkpoint provides insights into how cells respond to growth factors, DNA damage, and oncogenic stress, and offers targets for therapeutic intervention.
• Controls the commitment point for DNA replication, ensuring genomic stability.
• Integrates mitogenic signals with cell cycle machinery via cyclin D-CDK4/6 and cyclin E-CDK2.
• Dysregulation is a common event in cancer, driving uncontrolled proliferation.
• Serves as a target for CDK4/6 inhibitors in breast cancer therapy.
• Involved in developmental processes and tissue regeneration.
• Modulated by non-coding RNAs and micropeptides, adding layers of regulation.
• Conserved across species, from mammals to invertebrates.
• Key for understanding stem cell quiescence and activation.
• Provides biomarkers for cell cycle phase and proliferation.
• Enables high-throughput screening for anti-proliferative drugs.
What Happens During regulation of cell cycle G1/S phase transition?
Integration of Growth Signals
In simple terms: Cells listen to external growth signals before deciding to divide.
In early G1, mitogenic signals such as growth factors activate signaling cascades that lead to the expression of cyclin D, which partners with CDK4/6 to phosphorylate the retinoblastoma protein (RB). This initial phosphorylation partially inactivates RB, releasing some E2F transcription factors and allowing transcription of genes required for S phase entry. The architectural organization of chromatin and nuclear matrix also influences this process, as described by Stein et al..
CDK Activation and RB Hyperphosphorylation
In simple terms: Cyclin-CDK complexes add phosphate groups to RB, fully disabling it.
Cyclin E-CDK2 complexes further phosphorylate RB, leading to its hyperphosphorylation and complete inactivation. This releases E2F transcription factors, which drive the expression of genes necessary for DNA synthesis, including cyclin E itself, creating a positive feedback loop. The activity of CDK2 is tightly controlled by CDK inhibitors such as p21 and p27, which can block the G1/S transition in response to DNA damage or other stress signals.
E2F-Mediated Transcription
In simple terms: E2F proteins turn on the genes needed to copy DNA.
Once freed from RB, E2F transcription factors activate a battery of genes involved in nucleotide metabolism, DNA replication, and cell cycle progression. Inoshita et al. demonstrated that E2F1 regulates the G1/S transition in mesangial cells, highlighting its role in specific cell types. This transcriptional program ensures that the cell is fully equipped for DNA synthesis.
Checkpoint Control and Commitment
In simple terms: The cell checks for damage before committing to copy its DNA.
The G1/S transition is monitored by checkpoint pathways that can halt the cell cycle if DNA damage or other stresses are detected. For example, activation of p53 in response to DNA damage induces p21, which inhibits CDK2 and prevents RB phosphorylation, thereby blocking S phase entry. This checkpoint ensures that only cells with intact DNA proceed to replication.
Emerging Regulatory Layers
In simple terms: New players like micropeptides and non-coding RNAs fine-tune the transition.
Recent studies have identified additional regulators of the G1/S transition. For instance, the micropeptide SMIM30, encoded by LINC00998, promotes the G1/S transition by regulating cytosolic calcium levels. In oyster haemocytes, an ATP-binding cassette transporter (CgABCG2) modulates the G1/S phase transition, indicating conserved mechanisms across species. These findings expand the known regulatory network of GO:1902806.
Key Genes Involved in GO:1902806 regulation of cell cycle G1/S phase transition
The following genes and proteins are key players in the regulation of the G1/S phase transition, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCND1 | Cyclin D1, partners with CDK4/6 to phosphorylate RB | Overexpressed in many cancers; target for CDK4/6 inhibitors |
| CDK4 | Catalytic subunit that phosphorylates RB in complex with cyclin D | Target of palbociclib and other inhibitors |
| CDK6 | Similar to CDK4, phosphorylates RB | Target of CDK4/6 inhibitors |
| CCNE1 | Cyclin E, activates CDK2 to further phosphorylate RB | Amplified in some cancers; drives S phase entry |
| CDK2 | Kinase that partners with cyclin E to phosphorylate RB | Target for cancer therapy |
| RB1 | Retinoblastoma protein, gatekeeper of G1/S transition | Tumor suppressor; inactivated in many cancers |
| E2F1 | Transcription factor released from RB to activate S phase genes | Regulates G1/S in specific cell types |
| CDKN1A | p21, CDK inhibitor that blocks G1/S transition | Mediates p53-dependent cell cycle arrest |
| CDKN1B | p27, CDK inhibitor that regulates G1/S | Involved in quiescence and differentiation |
| MYC | Transcription factor that promotes cyclin D and E expression | Oncogene amplified in many cancers |
| TP53 | p53, induces p21 to block G1/S upon DNA damage | Tumor suppressor mutated in cancers |
| SMIM30 | Micropeptide from LINC00998 that regulates cytosolic calcium to promote G1/S | Emerging regulator |
| CgABCG2 | ABC transporter that modulates G1/S in oyster haemocytes | Invertebrate model |
| FSCN1 | Fascin, actin-bundling protein that modulates G1/S checkpoint regulators | Involved in breast cancer proliferation |
How Is regulation of cell cycle G1/S phase transition Regulated?
The regulation of the G1/S phase transition is controlled by multiple signaling pathways. Mitogenic signals through the RAS-MAPK and PI3K-AKT pathways induce cyclin D expression, while stress signals activate p53-p21 and TGF-beta-SMAD pathways that inhibit CDK activity. Additionally, non-coding RNAs and micropeptides can modulate the transition by affecting calcium signaling or other cellular processes. The interplay between these pathways ensures that the G1/S transition occurs only under favorable conditions.
regulation of cell cycle G1/S phase transition and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCND1 | Breast cancer, lymphoma | Knockout or overexpression in cancer cell lines |
| CDK4 | Breast cancer, liposarcoma | Point mutation (e.g., R24C) knock-in mice |
| RB1 | Retinoblastoma, osteosarcoma | Knockout in retinal or osteoblast cells |
| E2F1 | Mesangial proliferative glomerulonephritis | Knockout in mesangial cells |
| FSCN1 | Breast cancer proliferation | Knockdown or knockout in breast cancer cells |
Cancer
Dysregulation of the G1/S transition is a hallmark of cancer. Overexpression of cyclin D, CDK4/6, or cyclin E, or loss of RB or p21, leads to uncontrolled proliferation. For example, fascin (FSCN1) drives breast cancer cell proliferation partly by modulating G1/S checkpoint regulators. Targeting CDK4/6 with inhibitors has proven effective in breast cancer, highlighting the clinical relevance of this pathway.
Proliferative Disorders
Abnormal G1/S regulation is also implicated in non-cancerous proliferative disorders such as mesangial proliferative glomerulonephritis, where E2F1 plays a role. Understanding these mechanisms can inform therapeutic strategies for diseases characterized by excessive cell proliferation.
Developmental and Degenerative Diseases
Proper control of the G1/S transition is essential for development and tissue homeostasis. Its dysregulation can contribute to developmental abnormalities and may be involved in degenerative conditions where cell cycle re-entry is aberrant.
From regulation of cell cycle G1/S phase transition-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate G1/S transition? | CRISPR knockout in cell lines followed by flow cytometry |
| Does mutation Y affect CDK4 activity? | Point mutation knock-in (e.g., R24C) in cells |
| How does gene Z affect G1/S dynamics? | Knock-in of fluorescent reporter (PIP-FUCCI) |
| Does overexpression of gene W drive proliferation? | Doxycycline-inducible overexpression system |
| What is the role of non-coding RNA in G1/S? | CRISPR interference or knockout of lncRNA |
| Is the G1/S regulatory mechanism conserved? | Comparative studies in invertebrate models |
How to Study the regulation of cell cycle G1/S phase transition Process
| Method | What It Measures | Typical Application |
|---|---|---|
| PIP-FUCCI imaging | G1/S transition timing in live cells | Dynamic studies of cell cycle |
| Flow cytometry | DNA content and S phase fraction | Population analysis of cell cycle |
| EdU incorporation | DNA synthesis | Detection of S phase entry |
| CRISPR knockout screen | Genes required for G1/S | Identification of novel regulators |
| RNA-seq | Transcriptional changes | Profiling gene expression during G1/S |
| Proteomics | Protein abundance and modifications | Studying CDK substrates |
| Immunoblotting | Phosphorylation of RB, CDK levels | Validation of pathway activation |
| Luciferase reporter | E2F transcriptional activity | Measuring E2F activation |
Live-Cell Imaging
The PIP-FUCCI reporter allows real-time monitoring of cell cycle phases, including the G1/S transition, in living cells. This method enables precise delineation of phase transitions and can be combined with CRISPR knock-in of the reporter for dynamic studies.
Flow Cytometry
Flow cytometry with DNA dyes (e.g., propidium iodide) or EdU incorporation measures DNA content and S phase entry, providing population-level analysis of G1/S progression.
CRISPR Screens
Genome-wide CRISPR knockout or activation screens can identify genes that regulate the G1/S transition. These screens often use reporters or selection markers linked to S phase entry.
Transcriptomics and Proteomics
RNA-seq and proteomics can reveal changes in gene expression and protein abundance during the G1/S transition, identifying novel regulators and pathways.
How CRISPR Can Be Used to Study GO:1902806 regulation of cell cycle G1/S phase transition
Knockout
CRISPR knockout of candidate genes (e.g., CCND1, CDK4, E2F1) can determine their requirement for the G1/S transition. Cells are analyzed by flow cytometry or live-cell imaging to assess changes in S phase entry.
Point Mutation
Point mutations in genes such as CDK4 (e.g., R24C) that confer inhibitor resistance can be introduced via CRISPR knock-in to study their effects on G1/S regulation and drug response.
Knock-in
Knock-in of fluorescent reporters (e.g., PIP-FUCCI) or tags (e.g., HA-tag on CDK2) allows real-time tracking of G1/S transition and protein localization.
Overexpression
CRISPR activation (CRISPRa) or cDNA overexpression can drive ectopic expression of cyclins or CDKs to study their sufficiency in promoting G1/S transition and proliferation.
How EDITGENE Supports regulation of cell cycle G1/S phase transition Research
Researchers studying regulation of cell cycle G1/S phase transition-related genes often need to determine whether a candidate gene is causally involved in the transition or merely correlated with it. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such functional studies.
Contact EDITGENE today to design your custom CRISPR model for regulation of cell cycle G1/S phase transition research.
Frequently Asked Questions About regulation of cell cycle G1/S phase transition
What is GO:1902806?
GO:1902806 is a Gene Ontology term for regulation of cell cycle G1/S phase transition, defined as any signaling pathway that modulates cyclin-dependent protein kinase activity to control the switch from G1 to S phase.
What genes are involved in the G1/S phase transition?
Key genes include CCND1, CDK4, CDK6, CCNE1, CDK2, RB1, E2F1, CDKN1A (p21), and CDKN1B (p27).
Why is the G1/S transition important in cancer?
Dysregulation of the G1/S transition leads to uncontrolled proliferation, and many cancers have mutations in RB1, CCND1, or CDK4/6.
How is the G1/S transition regulated?
It is regulated by mitogenic signals that activate cyclin D-CDK4/6 and cyclin E-CDK2, which phosphorylate RB and release E2F transcription factors.
What methods are used to study the G1/S transition?
Methods include live-cell imaging with PIP-FUCCI, flow cytometry, CRISPR screens, and transcriptomics.
What is the role of E2F1 in the G1/S transition?
E2F1 is a transcription factor released from RB that activates genes required for DNA synthesis, and it regulates the G1/S transition in specific cell types such as mesangial cells.
How do CDK inhibitors affect the G1/S transition?
CDK inhibitors such as p21 and p27 bind to cyclin-CDK complexes and block their activity, preventing RB phosphorylation and S phase entry.
Can non-coding RNAs regulate the G1/S transition?
Yes, for example the micropeptide SMIM30 encoded by LINC00998 promotes the G1/S transition by regulating cytosolic calcium levels.
What is PIP-FUCCI?
PIP-FUCCI is a fluorescent reporter system that allows accurate delineation of cell cycle phase transitions, including G1/S, in living cells.
How can CRISPR be used to study the G1/S transition?
CRISPR can create knockouts, point mutations, knock-ins, or overexpression of genes to test their role in the G1/S transition.
Conclusion
The regulation of the cell cycle G1/S phase transition (GO:1902806) is a central process in cell proliferation, integrating diverse signals to ensure faithful DNA replication. Its dysregulation underlies cancer and other proliferative diseases, making it a key area of research. Advances in live-cell imaging and CRISPR technologies continue to uncover new regulators and mechanisms, offering potential therapeutic targets. EDITGENE supports this research with comprehensive CRISPR services to model and study G1/S regulatory genes.
References
- 1. Grant GD et al.. 2018. Accurate delineation of cell cycle phase transitions in living cells with PIP-FUCCI.. Cell Cycle 17(21-22):2496-2516 PMID: 30421640
- 2. Stein GS et al.. 2006. An architectural perspective of cell-cycle control at the G1/S phase cell-cycle transition.. J Cell Physiol 209(3):706-10 PMID: 17001681
- 3. Inoshita S et al.. 1999. Regulation of the G1/S transition phase in mesangial cells by E2F1.. Kidney Int 56(4):1238-41 PMID: 10504464
- 4. Yang JE et al.. 2023. LINC00998-encoded micropeptide SMIM30 promotes the G1/S transition of cell cycle by regulating cytosolic calcium level.. Mol Oncol 17(5):901-916 PMID: 36495128
- 5. 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
- 6. Hengstschläger M et al.. 1999. Cyclin-dependent kinases at the G1-S transition of the mammalian cell cycle.. Mutat Res 436(1):1-9 PMID: 9878675
- 7. Reed SI. 1997. Control of the G1/S transition.. Cancer Surv 29:7-23 PMID: 9338094
- 8. 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
