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ATM stabilizes DNA double-strand-break complexes during V(D)J recombination

Abstract

The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents1,2,3,4. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci5,6. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs1,2,3,4. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia.

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Figure 1: ATM-deficient pre-B cells exhibit defects in V(D)J recombination.
Figure 2: Hybrid join formation is not increased during rearrangement by deletion.
Figure 3: Coding ends are lost from post-cleavage complexes in ATM-deficient cells.
Figure 4: Increased aberrant resolution of coding ends, but not signal ends, in ATM-deficient cells.

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Acknowledgements

We thank M. Schlissel for pMX-RSS-GFP/IRES-hCD4. STI571 was provided by Novartis Pharmaceuticals and KU-55933 was provided by G. Smith at KuDOS Pharmaceuticals. We thank H. Virgin, K. Murphy and M. Krangel for critical review of the manuscript. This work is supported in part by grants from the National Institutes of Health (to B.P.S. and T.K.P.) and the Department of Army (T.K.P.). C.H.B. is a Pew Scholar in the Biomedical Sciences and a recipient of a Pilot Project Award from the American Cancer Society. B.P.S. is a recipient of a Research Scholar Award from the American Cancer Society. C.-Y.H. is supported by a post-doctoral training grant and A.L.B. a pre-doctoral training grant from the NIH.

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Correspondence to Barry P. Sleckman.

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Supplementary Notes

This file contains Supplementary Figures 1–19, Supplementary Methods and Supplementary Notes. The Supplementary Figures show the setup of the experimental system, data from additional cell lines, and controls for Figures 1-4. (PDF 2604 kb)

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Bredemeyer, A., Sharma, G., Huang, CY. et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 442, 466–470 (2006). https://doi.org/10.1038/nature04866

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