Roadworks of DNA Damage Bypass during and after Replication

Abstract

Duplication of the genome must be faithfully carried out in proliferating cells. DNA replication is the stage in which DNA damage becomes truly dangerous and potentially causes cell death or genomic instability. DNA damage bypass mechanisms have evolved as the`last minute' processes to protect the quality of genome replication from these risks. Damage bypass provides a highly ‰exible mechanism to tolerate various types of DNA damage during replication. Recent studies have highlighted that bypass mechanisms can be uncoupled from global genome replication: i.e., the time of action of DNA damage bypass is notˆxed at a particular point during genome replication. Although DNA damage bypass mechanisms are conserved throughout organisms, their regulation is diŠerent between prokaryotes and eukaryotes. On one hand, the bypass mechanisms of prokaryotes are mainly dependent on upregulation of transcripts under the SOS regulon. On the other hand, in eukaryotes, DNA damage bypass is activated by ubiquitylation of the replication sliding clamp, PCNA. This review starts with our understanding of the basis of lesion-bypassing mechanisms in the bacterial system, advances to recent views of the molecular mechanisms underlying eukaryotic DNA damage bypass and speciˆcally focuses on how the bypassing mechanisms provide temporally and structurally ‰exible functions.

Adaptive use of error‐prone DNA polymerases provides flexibility in genome replication during tumorigenesis

“…As the primary regulator of Y‐family polymerases, PCNA ubiquitylation recruits these polymerases to DNA, promoting damage‐bypass in many biological systems (Figure 1 ). 54 , 55 When replication is blocked by damaged DNA bases, the Rad6‐Rad18 E2‐E3 ligase complex is recruited to RPA‐coated ssDNA, 56 , 57 where it mono‐ubiquitylates PCNA to promote TLS. Subsequently, PCNA can be poly‐ubiquitylated by the Ubc13‐Mms2‐Rad5 complex to initiate damage bypass by HR‐dependent template switching.…”