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Minimizing the damage: repair pathways keep mitochondrial DNA intact

A Corrigendum to this article was published on 03 October 2012

This article has been updated

Key Points

  • Mitochondrial DNA is essential, but for many years mammalian mitochondria were thought to lack repair systems for their DNA. Now it is well established that base excision repair serves a key role in maintaining the integrity of the mitochondrial genome, and factors involved in all of the other major repair pathways have been assigned to mitochondria, albeit with differing degrees of confidence.

  • Much of the past, and indeed present, confusion arose from the fact that many mitochondrial DNA repair proteins are shared with the nucleus, and so the initial goal in assessing a protein's contribution to mitochondrial DNA repair is to establish it as a bona fide mitochondrial resident, and not merely a contaminant. Mitochondrial and nuclear DNA repair proteins that are encoded by the same gene can often be distinguished owing to the presence or absence of a mitochondrial targeting signal. Signal sequences may be generated through alternative splicing, alternative transcription initiation or alternative translation initiation.

  • The machinery of mitochondrial base excision repair overlaps considerably with that of the nucleus. By contrast, mismatch repair, a more recently accepted part of the DNA repair armoury, is less reliant on dually localized proteins.

  • The procedure for dealing with single-strand breaks in mitochondrial DNA is becoming clear, but there are still many gaps in our knowledge regarding mitochondrial double-strand break repair.

  • Human diseases and genetic manipulations are providing a wealth of new data on the factors contributing to mitochondrial DNA integrity, aiding the building of a comprehensive inventory of mitochondrial DNA repair factors.

  • As in other systems, mitochondrial DNA repair is likely to be integrated with the sister processes of replication and recombination. Aberrations in any or all these processes can give rise to pathological forms of mitochondrial DNA.

Abstract

Mitochondrial DNA (mtDNA) faces the universal challenges of genome maintenance: the accurate replication, transmission and preservation of its integrity throughout the life of the organism. Although mtDNA was originally thought to lack DNA repair activity, four decades of research on mitochondria have revealed multiple mtDNA repair pathways, including base excision repair, single-strand break repair, mismatch repair and possibly homologous recombination. These mtDNA repair pathways are mediated by enzymes that are similar in activity to those operating in the nucleus, and in all cases identified so far in mammals, they are encoded by nuclear genes.

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Figure 1: Base excision repair subpathways.
Figure 2: Mismatch repair.
Figure 3: Effect of mitochondrial DNA maintenance on mitochondrial homeostasis.

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Change history

  • 03 October 2012

    In the above article, the sentence “This study was the first to identify a protein (YB1) involved in mitochondrial MMR” incorrectly appeared below reference 107 instead of below reference 103 (de Souza-Pinto, N. C. et al. Novel DNA mismatch-repair activity involving YB-1 in human mitochondria. DNA Repair 8, 704–719 (2009)). This has been corrected online. The authors apologize for any confusion caused to readers.

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Acknowledgements

We thank S. Wood, M. Minczuk, J. Pohjoismäki and J. Poulton for insights and discussions. L.K. is the recipient of a Cambridge University Commonwealth Trust Fellowship, and work in the authors' laboratory is supported by the UK Medical Research Council.

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Glossary

N-glycosylic bond

The chemical bond between the base and the sugar of a nucleotide.

Thymine glycol

5,6-dihydroxydihydrothymine induced by chemical oxidation or ionizing radiation (an oxidative mutagen).

Apurinic/apyrimidinic site

(AP site). The site of an intact sugar-phosphate backbone after the nitrogenous base has been removed.

β-elimination mechanism

Incision of the DNA backbone between the sugar and the phosphate (that is, 3′ to the sugar of the damaged nucleotide), yielding a 3′-phospho-α,β-unsaturated aldehyde (3′ PUA) and a 5′ phosphate on either side of the strand break.

δ-elimination mechanism

Incision of the DNA backbone between the sugar and the phosphate (that is, 5′ to the sugar of the damaged nucleotide), removing the 3′ aldehyde from the β-elimination step to generate a 3′ phosphate adjacent to the 5′ phosphate.

Nucleotide incision repair

A glycosylase-independent mechanism of DNA strand cleavage, 5′ to the damaged base, generating a 3′ hydroxyl that can be used for DNA synthesis, with the 5′ side of the strand break acting as a substrate for flap endonuclease 1 cleavage.

Blocking residue

A 5′ phosphate and a 3′ hydroxyl are required for initiation of DNA synthesis and DNA ligation. A modification on either the 5′ or 3′ side of a strand break that does not support these processes is termed a blocking residue.

Okazaki fragment maturation

The removal of primers during replication of the lagging strand to produce suitable substrates for DNA ligase to generate a continuous nascent strand of DNA.

Nucleotide excision repair

A repair pathway that recognizes a diverse range of structural alterations that distort the shape of duplex DNA. After damage recognition, incisions are made on both sides of the lesion and a single-stranded DNA segment, containing the damage, is removed. The resulting DNA gap is subsequently filled in by DNA polymerase using the undamaged strand as a template.

Insertion–deletion loops

(IDLs). Insertion or deletion of nucleotides on one strand of duplex DNA, which results in looping out from the linear structure of DNA.

Microsatellites

Sequences of DNA that consist of repeating nucleotide units (1–6 base pairs in length). These can become longer or shorter owing to replication fork slippage, which can lead to frameshift mutations in genes, resulting in cancer predisposition.

Translesion bypass

The continuity of replication (or transcription), despite the presence of damage on the template DNA, with a high likelihood of errors that may lead to mutation.

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Kazak, L., Reyes, A. & Holt, I. Minimizing the damage: repair pathways keep mitochondrial DNA intact. Nat Rev Mol Cell Biol 13, 659–671 (2012). https://doi.org/10.1038/nrm3439

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