Publication Date:
2010-12-17
Description:
DNA double-strand breaks (DSBs) are generated by the recombination activating gene (RAG) endonuclease in all developing lymphocytes as they assemble antigen receptor genes. DNA cleavage by RAG occurs only at the G1 phase of the cell cycle and generates two hairpin-sealed DNA (coding) ends that require nucleolytic opening before their repair by classical non-homologous end-joining (NHEJ). Although there are several cellular nucleases that could perform this function, only the Artemis nuclease is able to do so efficiently. Here, in vivo, we show that in murine cells the histone protein H2AX prevents nucleases other than Artemis from processing hairpin-sealed coding ends; in the absence of H2AX, CtIP can efficiently promote the hairpin opening and resection of DNA ends generated by RAG cleavage. This CtIP-mediated resection is inhibited by gamma-H2AX and by MDC-1 (mediator of DNA damage checkpoint 1), which binds to gamma-H2AX in chromatin flanking DNA DSBs. Moreover, the ataxia telangiectasia mutated (ATM) kinase activates antagonistic pathways that modulate this resection. CtIP DNA end resection activity is normally limited to cells at post-replicative stages of the cell cycle, in which it is essential for homology-mediated repair. In G1-phase lymphocytes, DNA ends that are processed by CtIP are not efficiently joined by classical NHEJ and the joints that do form frequently use micro-homologies and show significant chromosomal deletions. Thus, H2AX preserves the structural integrity of broken DNA ends in G1-phase lymphocytes, thereby preventing these DNA ends from accessing repair pathways that promote genomic instability.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150591/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150591/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Helmink, Beth A -- Tubbs, Anthony T -- Dorsett, Yair -- Bednarski, Jeffrey J -- Walker, Laura M -- Feng, Zhihui -- Sharma, Girdhar G -- McKinnon, Peter J -- Zhang, Junran -- Bassing, Craig H -- Sleckman, Barry P -- A125195/PHS HHS/ -- AI074953/AI/NIAID NIH HHS/ -- AI47829/AI/NIAID NIH HHS/ -- CA136470/CA/NCI NIH HHS/ -- CA21765/CA/NCI NIH HHS/ -- NS37956/NS/NINDS NIH HHS/ -- P01 CA096832/CA/NCI NIH HHS/ -- P01 CA096832-08/CA/NCI NIH HHS/ -- R01 AI047829/AI/NIAID NIH HHS/ -- R01 AI047829-13/AI/NIAID NIH HHS/ -- R01 AI074953/AI/NIAID NIH HHS/ -- R01 AI074953-04/AI/NIAID NIH HHS/ -- R01 CA136470/CA/NCI NIH HHS/ -- R01 CA136470-04/CA/NCI NIH HHS/ -- R01 NS037956/NS/NINDS NIH HHS/ -- R01 NS037956-12/NS/NINDS NIH HHS/ -- R21 ES019779/ES/NIEHS NIH HHS/ -- R21 ES019779-02/ES/NIEHS NIH HHS/ -- T32 D007499/PHS HHS/ -- England -- Nature. 2011 Jan 13;469(7329):245-9. doi: 10.1038/nature09585. Epub 2010 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21160476" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Ataxia Telangiectasia Mutated Proteins
;
Carrier Proteins/*metabolism
;
Cell Cycle Proteins/*metabolism
;
Cell Line, Transformed
;
Chromatin/metabolism
;
*DNA Breaks, Double-Stranded
;
*DNA Repair
;
DNA-Binding Proteins/metabolism
;
Endonucleases
;
*G1 Phase
;
*Gene Rearrangement, B-Lymphocyte/genetics
;
Genomic Instability
;
Histones/deficiency/genetics/*metabolism
;
Intracellular Signaling Peptides and Proteins/metabolism
;
Lymphocytes/cytology/*metabolism
;
Mice
;
Nuclear Proteins
;
Precursor Cells, B-Lymphoid/metabolism
;
Protein-Serine-Threonine Kinases/metabolism
;
Recombination, Genetic/genetics
;
Substrate Specificity
;
Tumor Suppressor Proteins/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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