Regulation of the initiation of DNA replication upon DNA damage in eukaryotes

Abstract

Cycling cells must ensure homeostasis of the genetic information during repeated chromosome replication-segregation cycles. To guarantee genome stability in normal and DNA damage conditions the initiation of DNA replication in eukaryotes is regulated by the cell cycle machinery and the intra S-phase checkpoint (ISC). The cell cycle kinases CDK and DDK induce initiation specifically in S phase, and the ISC inhibits both kinase pathways, suppressing initiation upon DNA damage and replisome stalling to prevent the replication machinery from having to copy damaged DNA templates. Despite this ISC-mediated inhibition, dormant origins are allowed to fire in genomic regions that are actively engaged in replication when the DNA damage occurs. Forks from dormant origins can rescue replisomes that have stalled at DNA lesions, helping to ensure that no part of these replicating regions is left unreplicated in DNA damage conditions. This replisome rescue also helps prevent stalled and collapsed forks from causing genome rearrangements. In higher eukaryotes, these principles of regulating initiation upon DNA damage must be implemented into a particularly complex temporal regulation programme of genome replication. Molecular details of how the ISC, which poses an important barrier against tumour formation, achieves the regulation of initiation upon DNA damage is only beginning to emerge.