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A Pathway of Double-Strand Break Rejoining Dependent upon ATM, Artemis, and Proteins Locating to ¿-H2AX Foci

journal contribution
posted on 2023-06-08, 00:54 authored by Enriqueta Riballo, Martin Kühne, Nicole Rief, Aidan DohertyAidan Doherty, Graeme C M Smith, Mari´a-José Recio, Caroline Reis, Kirsten Dahm, Andreas Fricke, Andrea Krempler, Antony R Parker, Stephen P Jackson, Andrew Gennery, Penny Jeggo, Markus Löbrich
The hereditary disorder ataxia telangiectasia (A-T) is associated with striking cellular radiosensitivity that cannot be attributed to the characterized cell cycle checkpoint defects. By epistasis analysis, we show that ataxia telangiectasia mutated protein (ATM) and Artemis, the protein defective in patients with RS-SCID, function in a common double-strand break (DSB) repair pathway that also requires H2AX, 53BP1, Nbs1, Mre11, and DNA-PK. We show that radiation-induced Artemis hyperphosphorylation is ATM dependent. The DSB repair process requires Artemis nuclease activity and rejoins approximately 10% of radiation-induced DSBs. Our findings are consistent with a model in which ATM is required for Artemis-dependent processing of double-stranded ends with damaged termini. We demonstrate that Artemis is a downstream component of the ATM signaling pathway required uniquely for the DSB repair function but dispensable for ATM-dependent cell cycle checkpoint arrest. The significant radiosensitivity of Artemis-deficient cells demonstrates the importance of this component of DSB repair to survival.

History

Publication status

  • Published

Journal

Molecular Cell

ISSN

1097-2765

Issue

5

Volume

16

Page range

715-724

Pages

10.0

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Notes

Designed project. Work done in PJ lab. Wrote paper. Desrcibes discovery of a pathway of double strand break repair defective in several disorders.

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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