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

Publisher Website
Google Scholar
Abstract
Examination of the role of the ATM protein in oncogenic chromosomal translocations in the disease ataxia telangiectasia finds that ATM is involved directly in stabilizing a complex that occurs when DNA double-strand breaks are made in lymphocyte antigen receptor loci. When the complex is not stabilized, the DNA ends are able to undergo aberrant reactions that can lead to translocations. 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.

This publication has 30 references indexed in Scilit: