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The secret of S phase: How do cells decide when to enter DNA replication?
In the cell cycle, the S phase is considered a critical stage for DNA replication, a process that occurs between the G1 and G2 phases. How to accurately replicate the genome is an important factor in successful cell division, so the progression of S phase is strictly regulated and preserved.
Entry of cells into S phase is controlled by the G1 restriction point (R), and cells will commit to proceed through the remainder of the cell cycle only if nutrients and growth signals are sufficient.
Once the cell has passed this point, it will continue to enter S phase no matter how unfavorable the environmental conditions. This transition process is irreversible and is controlled by a series of molecular pathways that promote rapid and unidirectional changes in cell state.
For example, growth of yeast cells triggers the accumulation of the Cln3 cyclin, which forms a complex with the cyclin dependent kinase CDK2 to promote the expression of S phase genes.
Similar regulatory mechanisms also exist in mammalian cells. When receiving external growth signals in the G1 phase, cyclin D gradually accumulates and forms a complex with CDK4/6. The activated cyclin D-CDK4/6 complex releases the E2F transcription factor, initiates the expression of S phase genes, and further promotes the release of E2F, forming a positive feedback loop.
Initiation of DNA replicationDuring the M and G1 phases, cells assemble inactive pre-replication complexes (pre-RCs) at the replication origins of the genome. During S phase, the cell converts these proreplication complexes into active replication forks, initiating DNA replication. This process is dependent on the kinase activities of Cdc7 and various S-phase CDKs, which increase upon S-phase entry.
As Cdc7 and S-phase CDKs phosphorylate their respective substrates, a second set of replication factors bind to the pre-replication complex. Stable binding prompts the MCM helicase to open a small portion of the paternal DNA and recruit single-stranded DNA binding proteins. (such as RPA) and prepare for the loading of replicative DNA polymerase and PCNA sliding clamp.Activation of the prereplication complex is a tightly regulated and highly sequenced process.
Organizational structure re-establishment
During S phase, free histones synthesized by the cell are rapidly incorporated into new nucleosomes. This process is closely associated with the replication fork and occurs immediately before and after the replication complex. Behind the replication fork, reorganization of old nucleosomes is mediated by chromatin assembly factors (CAFs) that are loosely associated with replication proteins.
DNA Damage CheckpointThis process does not fully utilize the semiconservative mechanism seen in DNA replication, and labeling experiments show that nucleosome replication is mainly conservative.
During S phase, the cell continually checks its genome for abnormalities. When DNA damage is detected, three classic S-phase “checkpoint pathways” are initiated that delay or prevent further cell cycle progression. These pathways not only promote DNA repair but also prevent cells from entering mitosis when necessary.
For example, active ATR and ATM kinases can arrest cell cycle progression by promoting degradation of CDC25A.
Recent studies have shown that abnormal histone supply and problems with nucleosome assembly may also affect the progression of the S phase. When free histones are deficient in Drosophila cells, the S phase is prolonged and cells are permanently arrested in the G2 phase.
These striking findings reveal the complexity of the inner workings of S phase and its interaction with the cellular environment, and they raise questions about how cells make rapid decisions in a rapidly changing environment.
In the future of studying cell biology, can we gain a deeper understanding of how cells precisely control their life cycles and apply this knowledge to the medical field?
