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Activation of DSB processing requires phosphorylation of CtIP by ATR.

ABSTRACT: DNA double-strand breaks (DSBs) activate a DNA damage response (DDR) that coordinates checkpoint pathways with DNA repair. ATM and ATR kinases are activated sequentially. Homology-directed repair (HDR) is initiated by resection of DSBs to generate 3' single-stranded DNA overhangs. How resection and HDR are activated during DDR is not known, nor are the roles of ATM and ATR in HDR. Here, we show that CtIP undergoes ATR-dependent hyperphosphorylation in response to DSBs. ATR phosphorylates an invariant threonine, T818 of Xenopus CtIP (T859 in human). Nonphosphorylatable CtIP (T818A) does not bind to chromatin or initiate resection. Our data support a model in which ATM activity is required for an early step in resection, leading to ATR activation, CtIP-T818 phosphorylation, and accumulation of CtIP on chromatin. Chromatin binding by modified CtIP precedes extensive resection and full checkpoint activation.

SUBMITTER: Peterson SE

PROVIDER: S-EPMC3582837 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Activation of DSB processing requires phosphorylation of CtIP by ATR.

Peterson Shaun E SE Li Yinyin Y Wu-Baer Foon F Chait Brian T BT Baer Richard R Yan Hong H Gottesman Max E ME Gautier Jean J

Molecular cell 20121227 4

DNA double-strand breaks (DSBs) activate a DNA damage response (DDR) that coordinates checkpoint pathways with DNA repair. ATM and ATR kinases are activated sequentially. Homology-directed repair (HDR) is initiated by resection of DSBs to generate 3' single-stranded DNA overhangs. How resection and HDR are activated during DDR is not known, nor are the roles of ATM and ATR in HDR. Here, we show that CtIP undergoes ATR-dependent hyperphosphorylation in response to DSBs. ATR phosphorylates an inva ...[more]

PMID: 23273981

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