Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair.

Abstract	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	Lisa Woodbine, H Brunton, A A Goodarzi, A Shibata, P A Jeggo
Journal	Nucleic acids research (Nucleic Acids Res) Vol. 39 Issue 16 Pg. 6986-97 (Sep 01 2011) ISSN: 1362-4962 [Electronic] England
PMID	21596788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cell Cycle Proteins DNA-Binding Proteins Heterochromatin Histones Nuclear Proteins Reactive Oxygen Species Repressor Proteins Tumor Suppressor Proteins gamma-H2AX protein, mouse TRIM28 protein, human Tripartite Motif-Containing Protein 28 ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases DCLRE1C protein, human Endonucleases DNA Ligases DNA Ligase ATP
Topics	Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins (genetics, physiology) Cell Proliferation Cellular Senescence DNA Breaks, Double-Stranded DNA Ligase ATP DNA Ligases (physiology) DNA Repair DNA-Binding Proteins (genetics, physiology) Endonucleases Fibroblasts (enzymology, metabolism) Gene Knockdown Techniques Heterochromatin (metabolism) Histones (metabolism) Humans Mice Nuclear Proteins (genetics, physiology) Oxidative Stress Protein Serine-Threonine Kinases (genetics, physiology) Reactive Oxygen Species (metabolism) Repressor Proteins (metabolism) Tripartite Motif-Containing Protein 28 Tumor Suppressor Proteins (genetics, physiology)

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