ATM prevents unattended DNA double strand breaks on site and in generations to come

Abstract

Ataxia telangiectasia (A-T) is a disorder characterized by cerebellar degeneration, immunodeficiency, genomic instability, and genetic predisposition to lymphoid malignancies with translocations involving antigen receptor loci. The Ataxia Telangiectasia Mutated gene encodes the ATM kinase, a central transducer of DNA damage signals. Until recently, the etiology of the lymphoid phenotype in A-T patients and the mechanisms by which ATM ensures normal repair of DNA double strand break (DSB) intermediates during antigen receptor diversification reactions remained poorly understood. Last year, Bredemeyer et al. (Nature 2006; 442: 466-470) demonstrated that ATM stabilizes chromosomal V(D)J recombination DSB intermediates, facilitates DNA end joining, and prevents broken DNA ends from participating in chromosome deletions, inversions, and translocations. A more recent study by Callen et al. (Cell 2007; 130: 63-75) highlighted the importance of ATM-mediated checkpoints in blocking the long-term persistence and transmission of un-repaired DSBs in developing lymphocytes. Collectively, these results have provided complementary mechanistic insights into ATM functions in V(D)J recombination that can account for the lymphoid tumor-prone phenotype associated with A-T.