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DNA double-strand break resection occurs during non-homologous end joining in G1 but is distinct from resection during homologous recombination

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posted on 2023-06-09, 00:48 authored by Ronja Biehs, Monika Steinlage, Oliva Barton, Szilvia Juhász, Julia Künzel, Julian Spies, Atsushi Shibata, Penny Jeggo, Markus Löbrich
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.

Funding

RDF8: Identifying the origin of translocation-prone, ATM dependent DNA double-strand breaks using chromatin immunoprecipitation mass spectrometry; UNIVERSITY OF SUSSEX; RDF8-008

History

Publication status

  • Published

File Version

  • Published version

Journal

Molecular Cell

ISSN

1097-2765

Publisher

Elsevier

Issue

4

Volume

65

Page range

671-684

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-08-16

First Open Access (FOA) Date

2018-08-16

First Compliant Deposit (FCD) Date

2018-08-15

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