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Homologous recombination-mediated repair of DNA double-strand breaks operates in mammalian mitochondria

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Abstract

Mitochondrial DNA is frequently exposed to oxidative damage, as compared to nuclear DNA. Previously, we have shown that while microhomology-mediated end joining can account for DNA deletions in mitochondria, classical nonhomologous DNA end joining, the predominant double-strand break (DSB) repair pathway in nucleus, is undetectable. In the present study, we investigated the presence of homologous recombination (HR) in mitochondria to maintain its genomic integrity. Biochemical studies revealed that HR-mediated repair of DSBs is more efficient in the mitochondria of testes as compared to that of brain, kidney and spleen. Interestingly, a significant increase in the efficiency of HR was observed when a DSB was introduced. Analyses of the clones suggest that most of the recombinants were generated through reciprocal exchange, while ~ 30% of recombinants were due to gene conversion in testicular extracts. Colocalization and immunoblotting studies showed the presence of RAD51 and MRN complex proteins in the mitochondria and immunodepletion of MRE11, RAD51 or NIBRIN suppressed the HR-mediated repair. Thus, our results reveal importance of homologous recombination in the maintenance of mitochondrial genome stability.

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Acknowledgements

We thank Prof. Mercy J. Raman, Dr. Mridula Nambiar, Dr. Monica Pandey, Dr. Supriya Vartak, Dipayan Ghosh and SCR Lab members for critical reading of the manuscript. We would like to thank Dr. Umesh Varshney, IISc for providing us Tg1 bacterial strain. We also would like to thank Dr. Ganesh Nagaraju, IISc for providing us with the TFAM antibody. We thank the Central Animal and Confocal facilities of the Indian Institute of Science for the help. Financial assistance from CSIR, New Delhi (37(1579)/13/EMR-II) and from IISc-DBT partnership programme [DBT/BF/PR/INS/2011-12/IISc] for SCR is acknowledged. SD is supported by fellowship from IISc, Bangalore (India).

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  1. Department of Biochemistry, Indian Institute of Science, Bangalore, 560 012, India

    Sumedha Dahal, Shubham Dubey & Sathees C. Raghavan

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Dahal, S., Dubey, S. & Raghavan, S.C. Homologous recombination-mediated repair of DNA double-strand breaks operates in mammalian mitochondria. Cell. Mol. Life Sci. 75, 1641–1655 (2018). https://doi.org/10.1007/s00018-017-2702-y

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