Journal
NUCLEIC ACIDS RESEARCH
Volume 39, Issue 16, Pages 6986-6997Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkr331
Keywords
-
Categories
Funding
- Medical Research Council [G0500897]
- International Cancer Research [09-0018]
- Department of Health [RRX116]
- Wellcome Research Trust [084704/Z/08/Z]
- Wellcome Trust [084704/Z/08/Z] Funding Source: Wellcome Trust
- Medical Research Council [G0500897, G0801130B] Funding Source: researchfish
- MRC [G0500897] Funding Source: UKRI
Ask authors/readers for more resources
Ataxia telangiectasia (ATM) mutated and Artemis, the proteins defective in ataxia telangiectasia and a class of Radiosensitive-Severe Combined Immunodeficiency (RS-SCID), respectively, function in the repair of DNA double strand breaks (DSBs), which arise in heterochromatic DNA (HC-DSBs) following exposure to ionizing radiation (IR). Here, we examine whether they have protective roles against oxidative damage induced and/or endogenously induced DSBs. We show that DSBs generated following acute exposure of G0/G1 cells to the oxidative damaging agent, tert-butyl hydroperoxide (TBH), are repaired with fast and slow components of similar magnitude to IR-induced DSBs and have a similar requirement for ATM and Artemis. Strikingly, DSBs accumulate in ATM(-/-) mouse embryo fibroblasts (MEFs) and in ATM or Artemis-defective human primary fibroblasts maintained for prolonged periods under confluence arrest. The accumulated DSBs localize to HC-DNA regions. Collectively, the results provide strong evidence that oxidatively induced DSBs arise in HC as well as euchromatic DNA and that Artemis and ATM function in their repair. Additionally, we show that Artemis functions downstream of ATM and is dispensable for HC-relaxation and for pKAP-1 foci formation. These findings are important for evaluating the impact of endogenously arising DNA DSBs in ATM and Artemis-deficient patients.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available