ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection.
The immune system is capable of recognizing and eliminating an enormous array of pathogens due to the extremely diverse antigen receptor repertoire of T and B lymphocytes. However, the development of lymphocytes bearing receptors with unique specificities requires the generation of programmed double strand breaks (DSBs) coupled with bursts of proliferation, rendering lymphocytes susceptible to mutations contributing to oncogenic transformation. Consequently, mechanisms responsible for monitoring global genomic integrity must be activated during lymphocyte development to limit the oncogenic potential of antigen receptor locus recombination. Mutations in ATM (ataxia-telangiectasia mutated), a kinase that coordinates DSB monitoring and the response to DNA damage, result in impaired T-cell development and predispose to T-cell leukemia. Here, we review recent evidence providing insight into the mechanisms by which ATM promotes normal lymphocyte development and protects from neoplastic transformation.
Matei
Irina R
IR
Program in Developmental Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Guidos
Cynthia J
CJ
Danska
Jayne S
JS
D000818:Animals; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015329:Gene Rearrangement, T-Lymphocyte; D042822:Genomic Instability; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics / Q000276:immunology; D015458:Leukemia, T-Cell / Q000201:enzymology; D016399:Lymphoma, T-Cell / Q000201:enzymology; D038041:Lymphopoiesis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D045567:VDJ Recombinases
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D045567:VDJ Recombinases