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XB-ART-46434
Mol Cell 2013 Feb 21;494:657-67. doi: 10.1016/j.molcel.2012.11.020.
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Activation of DSB processing requires phosphorylation of CtIP by ATR.

Peterson SE , Li Y , Wu-Baer F , Chait BT , Baer R , Yan H , Gottesman ME , Gautier J .


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.

PubMed ID: 23273981
PMC ID: PMC3582837
Article link: Mol Cell
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: atm atr rbbp8
GO keywords: double-strand break repair

Disease Ontology terms: Seckel syndrome 1 [+]
OMIMs: SECKEL SYNDROME 1; SCKL1 [+]
References [+] :
Akamatsu, Molecular characterization of the role of the Schizosaccharomyces pombe nip1+/ctp1+ gene in DNA double-strand break repair in association with the Mre11-Rad50-Nbs1 complex. 2008, Pubmed