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DNA Repair (Amst). 2014 Jan;13:22-31. doi: 10.1016/j.dnarep.2013.11.002. Epub 2013 Dec 15.

Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia.

Author information

1
Department of Pharmacology and Physiology, New Jersey Medical School of UMDNJ, 185 South Orange Avenue, Medical Sciences Building, Newark, NJ 07103, United States.
2
Department of Genetics, Yale School of Medicine, 310 Cedar Street, BML 371, New Haven, CT 06520, United States.
3
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences (NIEHS), 111 TW Alexander Drive, Building 101, Durham, NC 27709, United States.
4
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.
5
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.

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.

KEYWORDS:

ATM; Ataxia Telangiectasia; DNA ligase 3; Mitochondria; Mitochondrial DNA repair

PMID:
24342190
PMCID:
PMC6211587
DOI:
10.1016/j.dnarep.2013.11.002
[Indexed for MEDLINE]
Free PMC Article

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