The human MSH5 (MutSHomolog 5) protein localizes to mitochondria and protects the mitochondrial genome from oxidative damage

MutS homologs play a central role in maintaining genetic stability. We show that MSH5 (MutSHomolog 5) is localized into the mitochondria of germ and somatic cells. This protein binds to mtDNA and interacts with the Twinkle helicase and the DNA polymerase gamma. hMSH5 stimulates mtDNA repair in response to DNA damage induced by oxidative stress. Furthermore, we observed a subsarcolemmal accumulation of hMSH5 in COX negative muscle fibers of patients presenting a mitochondrial myopathy. We report a novel localization for hMSH5 suggesting that this protein may have functions other than those known in meiotic recombination.

► hMSH5 localizes into the mitochondria of germ and somatic cells. ► It binds to mtDNA and interacts with Twinkle helicase and DNA Polymerase gamma. ► Oxidative lesions are repaired more efficiently when hMSH5 is overexpressed. ► MSH5 may accumulate into mitochondria in response to mitochondrial dysfunction.