title: Absence of p53-dependent apoptosis combined with nonhomologous end-joining deficiency leads to a severe diabetic phenotype in mice.
abstract: OBJECTIVE
  Regulation of pancreatic beta-cell mass is essential to preserve sufficient insulin levels for the maintenance of glucose homeostasis. Previously, we reported that DNA double-strand breaks (DSBs) resulting from nonhomologous end-joining (NHEJ) deficiency induce apoptosis and, when combined with p53 deficiency, progressed rapidly into lymphomagenesis in mice. Combination of NHEJ deficiency with a hypomorphic mutation, p53R172P, leads to the abrogation of apoptosis, upregulation of p21, and senescence in precursor lymphocytes. This was sufficient to prevent tumorigenesis. However, these mutant mice succumb to severe diabetes and die at an early age. The aim of this study was to determine the pathogenesis of diabetes in these mutant mice.
  
  
  METHODS
  We analyzed the morphology of the pancreatic islets and the function, proliferation rate, and senescence of beta-cells. We also profiled DNA damage and p53 and p21 expression in the pancreas.
  
  
  RESULTS
  NHEJ-p53R172P mutant mice succumb to diabetes at 3-5 months of age. These mice show a progressive decrease in pancreatic islet mass that is independent of apoptosis and innate immunity. We observed an accumulation of DNA damage, accompanied with increased levels of p53 and p21, a significant decrease in beta-cell proliferation, and cellular senescence in the mutant pancreatic islets.
  
  
  CONCLUSIONS
  Combined DSBs with an absence of p53-dependent apoptosis activate p53-dependent senescence, which leads to a diminished beta-cell self-replication, massive depletion of the pancreatic islets, and severe diabetes. This is a model that connects impaired DNA repair and accumulative DNA damage, a common phenotype in aging individuals, to the onset of diabetes.
authors.affiliation: Department of Immunology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Tavana
authors.forename: Nahum
authors.initials: N
authors.lastname: Puebla-Osorio
authors.forename: Mei
authors.initials: M
authors.lastname: Sang
authors.forename: Chengming
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency; D004268:DNA-Binding Proteins / Q000172:deficiency; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics*; D018149:Glucose Intolerance / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000172:deficiency / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010179:Pancreas / Q000473:pathology; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; D007328:Insulin; D016159:Tumor Suppressor Protein p53; C511788:XRCC4 protein, mouse; D011088:DNA Ligases; D000072481:DNA Ligase ATP