Pathological ribonuclease H1 causes R-loop depletion and aberrant DNA segregation in mitochondria

Gokhan Akman, Radha Desai, Laura J. Bailey, Takehiro Yasukawa, Ilaria Dalla Rosa, Romina Durigon, J. Bradley Holmes, Chloe F. Moss, Mara Mennuni, Henry Houlden, Robert J. Crouch, Michael G. Hanna, Robert D.S. Pitceathly, Antonella Spinazzola, Ian J. Holt

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


The genetic information in mammalian mitochondrial DNA is densely packed; there are no introns and only one sizeable noncoding, or control, region containing key cis-elements for its replication and expression. Many molecules of mitochondrial DNA bear a third strand of DNA, known as "7S DNA," which forms a displacement (D-) loop in the control region. Here we show that many other molecules contain RNA as a third strand. The RNA of these R-loops maps to the control region of the mitochondrial DNA and is complementary to 7S DNA. Ribonuclease H1 is essential for mitochondrial DNA replication; it degrades RNA hybridized to DNA, so the R-loop is a potential substrate. In cells with a pathological variant of ribonuclease H1 associated with mitochondrial disease, R-loops are of low abundance, and there is mitochondrial DNA aggregation. These findings implicate ribonuclease H1 and RNA in the physical segregation of mitochondrial DNA, perturbation of which represents a previously unidentified disease mechanism.

Original languageEnglish
Pages (from-to)E4276-E4285
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number30
Publication statusPublished - Jul 26 2016

All Science Journal Classification (ASJC) codes

  • General


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