ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1

ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1

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 Cdc...

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Bibliographic Details
Published in:Nature communications 2017-11, Vol.8 (1), p.1392-11, Article 1392
Main Authors: Moiseeva, Tatiana, Hood, Brian, Schamus, Sandy, O'Connor, Mark J, Conrads, Thomas P, Bakkenist, Christopher J
Format: Article
Language:eng
Subjects:
CHK1 protein
Damage detection
Damage prevention
Deoxyribonucleic acid
DNA
DNA damage
Exposure
Firing
Impact damage
Inhibitors
Kinases
Nucleotide sequence
Origins
Replication
Replication forks
Replication origins
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Summary: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.
ISSN:2041-1723
2041-1723