Roles of RAD18 in DNA Replication and Postreplication Repair

Abstract

In response to DNA damage and DNA-replication stress, eukaryotic cells activate two postreplication repair (PRR) mechanisms to facilitate completion of DNA synthesis. A DNA damage-tolerance mechanism termed "trans-lesion synthesis" (TLS) uses error-prone DNA polymerases to replicate damaged DNA templates. Alternatively, a DNA damage-avoidance mechanism termed "template switching" (TS) can perform error-free extension past the DNA lesion using an undamaged template. PRR allows cells to survive genotoxic injury from diverse DNA-damaging agents, although TLS and TS result in distinct genome stability outcomes. The E3 ubiquitin ligase RAD18 has apical roles in TLS- and TS-mediated genome maintenance. Here we review the mechanisms of RAD18 activation in response to DNA damage, its participation in TLS and TS, and the basis for integration of RAD18 activity with other elements of the DNA-damage response and the cell cycle. Finally, the potential impact of RAD18 on genome stability and tumorigenesis is considered.