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Mol Cell. 2017 Feb 16;65(4):671-684.e5. doi: 10.1016/j.molcel.2016.12.016. Epub 2017 Jan 26.

DNA Double-Strand Break Resection Occurs during Non-homologous End Joining in G1 but Is Distinct from Resection during Homologous Recombination.

Author information

1
Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
2
Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK; Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan. Electronic address: shibata.at@gunma-u.ac.jp.
3
Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK. Electronic address: p.a.jeggo@sussex.ac.uk.
4
Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany. Electronic address: lobrich@bio.tu-darmstadt.de.

Abstract

Canonical non-homologous end joining (c-NHEJ) repairs DNA double-strand breaks (DSBs) in G1 cells with biphasic kinetics. We show that DSBs repaired with slow kinetics, including those localizing to heterochromatic regions or harboring additional lesions at the DSB site, undergo resection prior to repair by c-NHEJ and not alt-NHEJ. Resection-dependent c-NHEJ represents an inducible process during which Plk3 phosphorylates CtIP, mediating its interaction with Brca1 and promoting the initiation of resection. Mre11 exonuclease, EXD2, and Exo1 execute resection, and Artemis endonuclease functions to complete the process. If resection does not commence, then repair can ensue by c-NHEJ, but when executed, Artemis is essential to complete resection-dependent c-NHEJ. Additionally, Mre11 endonuclease activity is dispensable for resection in G1. Thus, resection in G1 differs from the process in G2 that leads to homologous recombination. Resection-dependent c-NHEJ significantly contributes to the formation of deletions and translocations in G1, which represent important initiating events in carcinogenesis.

KEYWORDS:

DNA double-strand breaks; non-homologous end joining; nucleases; resection

PMID:
28132842
PMCID:
PMC5316416
DOI:
10.1016/j.molcel.2016.12.016
[Indexed for MEDLINE]
Free PMC Article

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