title: Deletion of Ku80 causes early aging independent of chronic inflammation and Rag-1-induced DSBs.
abstract: Animal models of premature aging are often defective for DNA repair. Ku80-mutant mice are disabled for nonhomologous end joining; a pathway that repairs both spontaneous DNA double-strand breaks (DSBs) and induced DNA DSBs generated by the action of a complex composed of Rag-1 and Rag-2 (Rag). Rag is essential for inducing DSBs important for assembling V(D)J segments of antigen receptor genes that are required for lymphocyte development. Thus, deletion of either Rag-1 or Ku80 causes severe combined immunodeficiency (scid) leading to chronic inflammation. In addition, Rag-1 induces breaks at non-B DNA structures. Previously we reported Ku80-mutant mice undergo premature aging, yet we do not know the root cause of this phenotype. Early aging may be caused by either defective repair of spontaneous DNA damage, defective repair of Rag-1-induced breaks or chronic inflammation caused by scid. To address this issue, we analyzed aging in control and Ku80-mutant mice deleted for Rag-1 such that both cohorts are scid and suffer from chronic inflammation. We make two observations: (1) chronic inflammation does not cause premature aging in these mice and (2) Ku80-mutant mice exhibit early aging independent of Rag-1. Therefore, this study supports defective repair of spontaneous DNA damage as the root cause of early aging in Ku80-mutant mice.
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245-3207, USA.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: Holcomb
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Paul
authors.initials: P
authors.lastname: Hasty
mesh_terms: D000367:Age Factors; D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D002908:Chronic Disease; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology; D017353:Gene Deletion; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000072200:Ku Autoantigen; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012720:Severity of Illness Index
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C064658:RAG-1 protein; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen