Intrinsic checkpoint deficiency during cell cycle re-entry from quiescence

Jacob Peter Matson; Amy M. House; Gavin D. Grant; Huaitong Wu; Joanna Perez; Jeanette Gowen Cook

Previous analysis by Daigh et al. indicated that cells released from G0 had increased endogenous replication stress in the first S phase compared to actively proliferating cells. This stress was detected as mid-S phase fluctuations in CDK activity plus markers of the replication stress response signaling pathway (Daigh et al., 2018) . Our findings here suggests a molecular mechanism by which that replication stress is generated. We propose that the underlicensed S phase after the first G1 has higher endogenous replication stress because fewer dormant origins are available. While we did not detect frank DNA damage markers in the absence of exogenous replication stress in our cells, we presume that endogenous stress was generated because these cells were uniquely sensitive to low dose gemcitabine. This hypersensitivity is a hallmark of cells that enter S phase while underlicensed (Woodward et al., 2006; Zimmerman et al., 2013) . The increased endogenous replication stress from too few licensed origins promotes genome instability from a higher frequency of stalled and unrescued replication forks.