S phase

S-phase (synthesis phase) is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this event in eukaryotes are highly conserved. This conservation makes the study of S-phase in model organisms such as Xenopus laevis embryos and budding yeast relevant to higher organisms.

S Phase Regulation
The G1/S transition is a major checkpoint in the regulation of the cell cycle. Depending on levels of nutrients, energy and external factors, cells must decide to enter the cell cycle or move into a non-dividing state known as G0 phase. This transition, as with all of the major checkpoint transitions in the cell cycle, is signaled by cyclins and cyclin dependent kinase (CDKs). The pulse of G1/S cyclins causes CLN3-Cdk1 to activate Cln1/2, (Start point (yeast)) as well as Clb5/6 at the initiation of S-phase. This pathway contains 2 positive feedback loops, allowing for rapid, unidirectional movement into S-phase. Redundant pathways like this are not uncommon because they allow for tuning the output of the system and often lead to faster genetic evolution.

DNA Replication
The major event in S-phase is DNA replication. The goal of this process is to create exactly two identical semi-conserved chromosomes. The cell prevents more than one replication from occurring by loading pre-replication complexes onto the DNA at replication origins during G1-phase which are dismantled in S-phase as replication begins. In budding yeast, Cdc6 is degraded, Orc2/6 are phosphorylated and mcm proteins are excluded from the nucleus, preventing re-attachment of the replication machinery (DNA polymerase) to the DNA after initiation. Incredibly, DNA synthesis can occur as fast as 100 nucleotides/second and must be as accurate as 1 wrong base in 109 nucleotide additions.

DNA Damage
Damage to DNA is detected and fixed during S-phase. When the replication fork comes upon damaged DNA, ATR, a protein kinase, is activated. This kinase initiates several complex downstream pathways causing a halt in the initiation of new replication origins, prevention of mitosis and replication fork stabilization in order to keep the replication bubble open and DNA polymerase complex attached while the damage is being fixed.