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DNA Repair (Amst). 2014 Apr;16:44-53. doi: 10.1016/j.dnarep.2014.01.015. Epub 2014 Feb 27.

Overexpression of DNA ligase III in mitochondria protects cells against oxidative stress and improves mitochondrial DNA base excision repair.

Author information

1
Center for Healthy Aging, SUND, University of Copenhagen, Denmark.
2
Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Boulevard, Baltimore, USA.
3
Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Boulevard, Baltimore, USA; Center for Healthy Aging, SUND, University of Copenhagen, Denmark. Electronic address: vbohr@nih.gov.

Abstract

Base excision repair (BER) is the most prominent DNA repair pathway in human mitochondria. BER also results in a temporary generation of AP-sites, single-strand breaks and nucleotide gaps. Thus, incomplete BER can result in the generation of DNA repair intermediates that can disrupt mitochondrial DNA replication and transcription and generate mutations. We carried out BER analysis in highly purified mitochondrial extracts from human cell lines U2OS and HeLa, and mouse brain using a circular DNA substrate containing a lesion at a specific position. We found that DNA ligation is significantly slower than the preceding mitochondrial BER steps. Overexpression of DNA ligase III in mitochondria improved the rate of overall BER, increased cell survival after menadione induced oxidative stress and reduced autophagy following the inhibition of the mitochondrial electron transport chain complex I by rotenone. Our results suggest that the amount of DNA ligase III in mitochondria may be critical for cell survival following prolonged oxidative stress, and demonstrate a functional link between mitochondrial DNA damage and repair, cell survival upon oxidative stress, and removal of dysfunctional mitochondria by autophagy.

KEYWORDS:

Autophagy; Cell survival; Mitochondrial DNA repair intermediates; Oxidative stress

PMID:
24674627
PMCID:
PMC5156482
DOI:
10.1016/j.dnarep.2014.01.015
[Indexed for MEDLINE]
Free PMC Article

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