Loss of Rad52 partially rescues tumorigenesis and T-cell maturation in Atm-deficient mice.
Ataxia Telangiectasia (A-T) is an autosomal recessive disease caused by loss of function of the protein kinase ATM. Atm-deficient mice display several phenotypes consistent with the human disease, including predisposition to cancer, growth retardation, cell-proliferation defects and infertility. A-T patients have a several hundred fold increased risk of developing lymphomas and leukemias, which are typically highly invasive. By reducing homologous recombination through genetic deletion of the Rad52 protein, we were able to decrease substantially the development of T-cell lymphomas in Atm-/- mice, resulting in an increased life span of the double mutant mice. Additionally, we were able to partially rescue the T-cell development of Atm-/- mice. Other phenotypes, including growth defects, genomic instability, infertility and radiosensitivity, were not rescued. Our results suggest that excessive recombination is an important contributor to tumorigenesis in A-T.
Treuner
Kai
K
The Salk Institute for Biological Studies, The Laboratory of Genetics, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Helton
Rob
R
Barlow
Carrolee
C
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000276:immunology; D064007:Ataxia Telangiectasia Mutated Proteins; D001835:Body Weight / Q000235:genetics; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D008136:Longevity; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D051721:Rad52 DNA Repair and Recombination Protein; D011995:Recombination, Genetic; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology; D013997:Time Factors; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051721:Rad52 DNA Repair and Recombination Protein; C497196:Rad52 protein, mouse; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases