title: Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia.
abstract: Ataxia Telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer. A-T is caused by mutations in the kinase ATM, a master regulator of the DNA double-strand break response. In addition to DNA-damage signaling defects, A-T cells display mitochondrial dysfunction that is thought to contribute to A-T pathogenesis. However, the molecular mechanism leading to mitochondrial dysfunction in A-T remains unclear. Here, we show that lack of ATM leads to reduced mitochondrial DNA (mtDNA) integrity and mitochondrial dysfunction, which are associated to defective mtDNA repair. While protein levels of mtDNA repair proteins are essentially normal, in the absence of ATM levels specifically of DNA ligase III (Lig3), the only DNA ligase working in mitochondria is reduced. The reduction of Lig3 is observed in different A-T patient cells, in brain and pre-B cells derived from ATM knockout mice as well as upon transient or stable knockdown of ATM. Furthermore, pharmacological inhibition of Lig3 in wild type cells phenocopies the mtDNA repair defects observed in A-T patient cells. As targeted deletion of LIG3 in the central nervous system causes debilitating ataxia in mice, reduced Lig3 protein levels and the consequent mtDNA repair defect may contribute to A-T neurodegeneration. A-T is thus the first disease characterized by diminished Lig3.
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School of UMDNJ, 185 South Orange Avenue, Medical Sciences Building, Newark, NJ 07103, United States.
authors.forename: Nilesh K
authors.initials: NK
authors.lastname: Sharma
authors.affiliation: Department of Genetics, Yale School of Medicine, 310 Cedar Street, BML 371, New Haven, CT 06520, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Lebedeva
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School of UMDNJ, 185 South Orange Avenue, Medical Sciences Building, Newark, NJ 07103, United States.
authors.forename: Terace
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School of UMDNJ, 185 South Orange Avenue, Medical Sciences Building, Newark, NJ 07103, United States.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Kovalenko
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences (NIEHS), 111 TW Alexander Drive, Building 101, Durham, NC 27709, United States.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Stumpf
authors.affiliation: Department of Genetics, Yale School of Medicine, 310 Cedar Street, BML 371, New Haven, CT 06520, United States; Department of Pathology, Yale School of Medicine, 310 Cedar Street, BML 371, New Haven, CT 06520, United States.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School of UMDNJ, 185 South Orange Avenue, Medical Sciences Building, Newark, NJ 07103, United States. Electronic address: Janine.santos@nih.gov.
authors.forename: Janine H
authors.initials: JH
authors.lastname: Santos
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor; D002460:Cell Line; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009420:Nervous System / Q000378:metabolism / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins
chemical_list: D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D007976:Leupeptins; D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human; C000618818:Lig3 protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: ATM; Ataxia Telangiectasia; DNA ligase 3; Mitochondria; Mitochondrial DNA repair