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

Tatiana Moiseeva, Brian Hood, Sandy Schamus, Mark J. O'Connor, Thomas P. Conrads, Christopher J. Bakkenist*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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.

Original languageEnglish
Article number1392
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2017
Externally publishedYes

Fingerprint

Dive into the research topics of 'ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1'. Together they form a unique fingerprint.

Cite this