1. Department of Pathology and Immunology and
2. Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA
3. Department of Pathology and Laboratory Medicine and
4. Division of Allergy and Immunology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
5. Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania 19104, USA

Correspondence to: Barry P. Sleckman¹ Correspondence and requests for materials should be addressed to B.P.S. (Email: Sleckman@immunology.wustl.edu).

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 agents^{1, 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 loci^{5, 6}. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs^{1, 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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