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p53 functions in the incorporation step in DNA base excision repair in mouse liver mitochondria

Oncogene volume 23, pages 6559–6568 (2004)Cite this article

Abstract

The tumor suppressor p53 protein stimulates nuclear base excision repair (BER) in vitro. In response to certain cellular stresses, p53 translocates to mitochondria, where it can trigger an apoptotic response. However, a potential role for p53 in modulating mitochondrial DNA repair has not yet been examined. In this study, we show that p53 also modulates mitochondrial BER. Uracil-initiated BER incorporation, which measures flux through the entire BER pathway, was lower in mitochondrial extracts from nonstressed p53 knockout mice than in wild type. The addition of recombinant p53 complemented the BER incorporation in p53 knockout extracts and stimulated BER in wt extracts. The activities of three major mitochondrial DNA glycosylases were similar in extracts from wild-type and knockout animals. Likewise, AP endonuclease activity was unaffected by the absence of p53. Gel shift experiments with recombinant p53 demonstrated that p53 did not bind to the uracil-containing substrate used in the repair assay. Polymerase γ gap-filing activity was less efficient in p53 knockout extracts, but it was complemented with the addition of recombinant p53. Thus, we conclude that p53 may participate in mtBER by stimulating the repair synthesis incorporation step.

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Abbreviations

AP:

apurinic/apyrimidinic

BER:

base excision repair

MLME:

mouse liver mitochondrial extract

MLNE:

mouse liver nuclear extract

mtBER:

mitochondrial base excision repair

mtDNA:

mitochondrial DNA

NTH1:

endonuclease III homologue 1

OGG1:

oxoguanine DNA glycosylase

Pol γ:

DNA polymerase gamma

U:

uracil

UDG:

uracil DNA glycosylase

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Acknowledgements

We thank Drs Cayetano Von Kobbe and Syed Imam for the critical reading of this manuscript. We also thank Dr Draginja Djurickovic (NCIFCRF) for transferring the animals.

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Authors and Affiliations

  1. Laboratory of Molecular Gerontology, NIA-IRP, National Institutes of Health, Baltimore, 21224, MD, USA

    Nadja C de Souza-Pinto & Vilhelm A Bohr

  2. Laboratory of Human Carcinogenesis, CTR, NCI, National Institutes of Health, Bethesda, 20892, MD, USA

    Curtis C Harris

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  1. Nadja C de Souza-Pinto
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  2. Curtis C Harris
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  3. Vilhelm A Bohr
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Correspondence to Vilhelm A Bohr.

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de Souza-Pinto, N., Harris, C. & Bohr, V. p53 functions in the incorporation step in DNA base excision repair in mouse liver mitochondria. Oncogene 23, 6559–6568 (2004). https://doi.org/10.1038/sj.onc.1207874

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