G1/S transition

• The G1/S transition represents one of the most decisive control points in the cell cycle, marking the moment when a cell commits to entering S phase and replicating its DNA. During early G1, the cell is still responsive to external cues such as growth factors, nutrient availability, and stress signals. However, as it approaches the G1/S boundary, it reaches the restriction point (in mammalian cells) or Start (in yeast), after which progression becomes independent of external mitogenic stimulation. Passing this point commits the cell to DNA synthesis and ultimately to completing the entire cycle, making the G1/S transition a biological “point of no return.”
• At the molecular level, the transition is driven by the coordinated activation of Cyclin D–CDK4/6 and Cyclin E–CDK2 complexes. These kinases progressively phosphorylate the retinoblastoma protein (Rb), causing it to release E2F transcription factors. Once freed, E2F activates a suite of genes required for S‑phase entry, including DNA polymerases, replication licensing factors, and nucleotide biosynthesis enzymes. This ensures that the cell has the necessary machinery and metabolic resources to replicate its genome accurately and efficiently.
• The G1/S transition also functions as a major genome‑protection checkpoint. If the cell detects DNA damage, oxidative stress, oncogenic signalling, or insufficient nutrients, inhibitory proteins such as p21, p27, and p16 suppress CDK activity, preventing premature entry into S phase. The tumour suppressor p53 plays a central role in this response by activating transcription of CDK inhibitors and promoting DNA repair pathways. Proper regulation of the G1/S transition is therefore essential for maintaining genomic stability, coordinating growth with division, and preventing uncontrolled proliferation. Defects in this checkpoint—particularly in Rb, p53, or CDK regulation—are hallmarks of many cancers.

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Last updated: 20th August 2026