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Factors determining DNA double-strand break repair pathway choice in G2 phase.

Shibata, Atsushi and Conrad, Sandro and Birraux, Julie and Geuting, Verena and Barton, Olivia and Ismail, Amani and Kakarougkas, Andreas and Meek, Katheryn and Taucher-Scholz, Gisela and Löbrich, Markus and Jeggo, Penny A. (2011):
Factors determining DNA double-strand break repair pathway choice in G2 phase.
In: The EMBO journal, ISSN 1460-2075,
[Article]

Abstract

DNA non-homologous end joining (NHEJ) and homologous recombination (HR) function to repair DNA double-strand breaks (DSBs) in G2 phase with HR preferentially repairing heterochromatin-associated DSBs (HC-DSBs). Here, we examine the regulation of repair pathway usage at two-ended DSBs in G2. We identify the speed of DSB repair as a major component influencing repair pathway usage showing that DNA damage and chromatin complexity are factors influencing DSB repair rate and pathway choice. Loss of NHEJ proteins also slows DSB repair allowing increased resection. However, expression of an autophosphorylation-defective DNA-PKcs mutant, which binds DSBs but precludes the completion of NHEJ, dramatically reduces DSB end resection at all DSBs. In contrast, loss of HR does not impair repair by NHEJ although CtIP-dependent end resection precludes NHEJ usage. We propose that NHEJ initially attempts to repair DSBs and, if rapid rejoining does not ensue, then resection occurs promoting repair by HR. Finally, we identify novel roles for ATM in regulating DSB end resection; an indirect role in promoting KAP-1-dependent chromatin relaxation and a direct role in phosphorylating and activating CtIP.

Item Type: Article
Erschienen: 2011
Creators: Shibata, Atsushi and Conrad, Sandro and Birraux, Julie and Geuting, Verena and Barton, Olivia and Ismail, Amani and Kakarougkas, Andreas and Meek, Katheryn and Taucher-Scholz, Gisela and Löbrich, Markus and Jeggo, Penny A.
Title: Factors determining DNA double-strand break repair pathway choice in G2 phase.
Language: English
Abstract:

DNA non-homologous end joining (NHEJ) and homologous recombination (HR) function to repair DNA double-strand breaks (DSBs) in G2 phase with HR preferentially repairing heterochromatin-associated DSBs (HC-DSBs). Here, we examine the regulation of repair pathway usage at two-ended DSBs in G2. We identify the speed of DSB repair as a major component influencing repair pathway usage showing that DNA damage and chromatin complexity are factors influencing DSB repair rate and pathway choice. Loss of NHEJ proteins also slows DSB repair allowing increased resection. However, expression of an autophosphorylation-defective DNA-PKcs mutant, which binds DSBs but precludes the completion of NHEJ, dramatically reduces DSB end resection at all DSBs. In contrast, loss of HR does not impair repair by NHEJ although CtIP-dependent end resection precludes NHEJ usage. We propose that NHEJ initially attempts to repair DSBs and, if rapid rejoining does not ensue, then resection occurs promoting repair by HR. Finally, we identify novel roles for ATM in regulating DSB end resection; an indirect role in promoting KAP-1-dependent chromatin relaxation and a direct role in phosphorylating and activating CtIP.

Journal or Publication Title: The EMBO journal
Divisions: 10 Department of Biology
10 Department of Biology > Radiation Biology and DNA Repair
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Date Deposited: 14 Mar 2011 15:19
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