Journal
DNA REPAIR
Volume 13, Issue -, Pages 22-31Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2013.11.002
Keywords
ATM; Mitochondria; Mitochondrial DNA repair; DNA ligase 3; Ataxia Telangiectasia
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Funding
- Department of Defense, Army Research Office [56027LS]
- NIH [NS56206]
- A-T Children's Project
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS056206] Funding Source: NIH RePORTER
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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. Published by Elsevier B.V.
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