ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1
By T. Moiseeva, B. Hood, Sandra Schamus, Mark J. O'Connor, Thomas P. Conrads, C. Bakkenist. 2017
83 citations recorded by the source corpus.
ATR kinase activity slows replication forks and prevents origin firing in damaged cells. Here we describe proteomic analyses that identified mechanisms through which ATR kinase inhibitors induce unscheduled origin firing in undamaged cells. ATR-Chk1 inhibitor-induced origin firing is mediated by Cdc7 kinase through previously undescribed phosphorylations on GINS that induce an association between GINS and And-1. ATR-Chk1 inhibitor-induced origin firing is blocked by prior exposure to DNA damaging agents showing that the prevention of origin firing does not require ongoing ATR activity. In contrast, ATR-Chk1 inhibitor-induced origins generate additional replication forks that are targeted by subsequent exposure to DNA damaging agents. Thus, the sequence of administration of an ATR kinase inhibitor and a DNA damaging agent impacts the DNA damage induced by the combination. Our experiments identify competing ATR and Cdc7 kinase-dependent mechanisms at replication origins in human cells. ATR kinase activity is essential for slowing replication forks and preventing DNA replication in cells with DNA damage. Here the authors show that ATR inhibition leads to Cdc7 phosphorylation of GINS, leading to origin firing.
Subfields: Cell Biology, Molecular Biology, Oncology
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Citations in the corpus
- In silico protein interaction screening uncovers DONSON’s role in replication initiation (2023, background): “These replication initiation phenotypes were not due to defective checkpoint signaling because inhibiting ATR has the opposite effect of DONSON deficiency in that it stimulates initiation events (origin firing) ( 40 ) and enhances CDC45 and GINS recruitment to chromatin (fig.”
- The non-catalytic role of DNA polymerase epsilon in replication initiation in human cells (2022, background): “In agreement with these data we found that cat (1-1261) and ΔcatΔZF (1262-2157) constructs were unable to pull down POLE2.”