S phase

thumb|upright=1.35|Asymmetry in the synthesis of leading and lagging strands

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G₁ phase and G₂ phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

Regulation

Entry into S-phase is controlled by the G1 restriction point (R), which commits cells to the remainder of the cell-cycle if there is adequate nutrients and growth signaling. This transition is essentially irreversible; after passing the restriction point, the cell will progress through S-phase even if environmental conditions become unfavorable. The Cln3-CDK2 complex promotes transcription of S-phase genes by inactivating the transcriptional repressor Whi5. During S-phase, the cell converts pre-RCs into active replication forks to initiate DNA replication. Redundant origins may increase the flexibility of DNA replication, allowing cells to control the rate of DNA synthesis and respond to replication stress. NPAT is activated by phosphorylation and recruits the Tip60 chromatin remodeling complex to the promoters of histone genes. SLBP binding is required for efficient processing, export, and translation of histone mRNAs, allowing it to function as a highly sensitive biochemical "switch". This immediately halts histone production and prevents a toxic buildup of free histones.

Nucleosome replication

thumb|239x239px|Conservative reassembly of core H3/H4 nucleosome behind the replication fork.|alt=

Free histones produced by the cell during S-phase are rapidly incorporated into new nucleosomes. This process is closely tied to the replication fork, occurring immediately in "front" and "behind" the replication complex. Translocation of MCM helicase along the leading strand disrupts parental nucleosome octamers, resulting in the release of H3-H4 and H2A-H2B subunits. Reassembly of nucleosomes behind the replication fork is mediated by chromatin assembly factors (CAFs) that are loosely associated with replication proteins. Though not fully understood, the reassembly does not appear to utilize the semi-conservative scheme seen in DNA replication.

1. The Replication Checkpoint detects stalled replication forks by integrating signals from RPA, ATR Interacting Protein (ATRIP), and RAD17.

In addition to these canonical checkpoints, recent evidence suggests that abnormalities in histone supply and nucleosome assembly can also alter S-phase progression. Depletion of free histones in Drosophila cells dramatically prolongs S-phase and causes permanent arrest in G2-phase.