The Licensing Factor Cdt1 Links Cell Cycle Progression to the DNA Damage Response.

The maintenance of genome integrity is essential for cellular survival and propagation. It relies upon the accurate and timely replication of the genetic material, as well as the rapid sensing and repairing of damage to DNA. Uncontrolled DNA replication and unresolved DNA lesions contribute to genomic instability and can lead to cancer. Chromatin licensing and DNA replication factor 1 (Cdt1) is essential for loading the minichromosome maintenance 2-7 helicase complex onto chromatin exclusively during the G(1) phase of the cell cycle, thus limiting DNA replication to once per cell cycle. Upon DNA damage, Cdt1 rapidly accumulates to sites of damage and is subsequently poly-ubiquitinated by the cullin 4-RING E3 ubiquitin ligase complex, in conjunction with the substrate recognition factor Cdt2 (CRL4(Cdt2)), and targeted for degradation. We here discuss the cellular functions of Cdt1 and how it may interlink cell cycle regulation and DNA damage response pathways, contributing to genome stability.