Replisome dysfunction upon inducible TIMELESS degradation synergizes with ATR inhibition to trigger replication catastrophe.

ABSTRACT: The structure of DNA replication forks is preserved by TIMELESS (TIM) in the fork protection complex (FPC) to support seamless fork progression. While the scaffolding role of the FPC to couple the replisome activity is much appreciated, the detailed mechanism whereby inherent replication fork damage is sensed and counteracted during DNA replication remains largely elusive. Here, we implemented an auxin-based degron system that rapidly triggers inducible proteolysis of TIM as a source of endogenous DNA replication stress and replisome dysfunction to dissect the signaling events that unfold at stalled forks. We demonstrate that acute TIM degradation activates the ATR-CHK1 checkpoint, whose inhibition culminates in replication catastrophe by single-stranded DNA accumulation and RPA exhaustion

SUBMITTER: Patel JA 

PROVIDER: S-EPMC10325925 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature