Chk1 loss creates replication barriers that compromise cell survival independently of excess origin firing

ABSTRACT: The effectiveness of Checkpoint kinase 1 (Chk1) inhibitors at killing cancer cells is considered to be fully dependent on their effect on DNA replication initiation. Chk1 inhibition boosts origin firing, presumably limiting the availability of nucleotides and in turn provoking the slow-down and subsequent collapse of forks, thus decreasing cell viability. Here we show that slow fork progression in Chk1-inhibited cells is not an indirect effect of excess new origin firing. Instead, fork slow-down results from the accumulation of replication barriers, whose bypass is impeded by CDK-dependent phosphorylation of the specialized DNA polymerase eta (Poleta). Also in contrast to the linear model, the accumulation of DNA damage in Chk1-deficient cells depends on origin density but is largely indep

SUBMITTER: Dr. Marina, Alejandra González Besteiro 

PROVIDER: S-SCDT-EMBOJ-2018-101284 | biostudies-other |

REPOSITORIES: biostudies-other