PT  - JOURNAL ARTICLE
AU  - Marten Hornsveld
AU  - Femke M Feringa
AU  - Lenno Krenning
AU  - Jeroen van den Berg
AU  - Lydia MM Smits
AU  - Nguyen BT Nguyen
AU  - Maria J Rodriguez-Colman
AU  - Tobias B Dansen
AU  - Rene H Medema
AU  - Boudewijn MT Burgering
TI  - A FOXO-dependent replication checkpoint restricts proliferation of damaged cells
AID  - 10.1101/2020.01.09.900225
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.09.900225
4099  - http://biorxiv.org/content/early/2020/01/09/2020.01.09.900225.short
4100  - http://biorxiv.org/content/early/2020/01/09/2020.01.09.900225.full
AB  - DNA replication is challenged by numerous exogenous and endogenous factors that can interfere with the progression of replication forks. Stalling or slowing of the replication fork as a result of replication stress leads to formation of aberrant single-stranded DNA (ssDNA) stretches and potentially DNA double-stranded-breaks (DSBs). Accumulation of ssDNA activates the ATR-dependent DNA replication stress checkpoint response that slows progression from S/G2- to M-phase to protect genomic integrity (1). However, whether mild replication stress restricts proliferation remains controversial (2–6). Here we identify a novel cell cycle exit mechanism, that prevents S/G2 phase arrested cells from undergoing mitosis after exposure to mild replication stress through premature activation of the CDH1 bound Anaphase Promoting Complex / Cyclosome (APC/CCDH1). We find that replication stress causes a gradual decrease of the levels of the APC/CCDH1 inhibitor EMI1/FBXO5 through Forkhead Box O (FOXOs) mediated repression of its transcriptional regulator E2F1. By doing so, FOXOs limit the time during which the replication stress checkpoint is reversible, and thereby play an important role in maintaining genomic stability.