Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 30, Pages E4276-E4285Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1600537113
Keywords
RNase H1; R-loop; mitochondrial DNA; DNA segregation; mitochondrial disease
Categories
Funding
- European Commission, MEET Project Grant [317433]
- Medical Research Council (MRC) Intramural Award
- MRC Senior Non-Clinical Fellowship [MC_ PC_ 13029]
- MRC Centre for Neuromuscular Diseases Grant [G0601943]
- UK National Health Service Specialised Service for Rare Mitochondrial Diseases of Adults and Children
- National Institute for Health Research University College London Hospitals/University College London Biomedical Research Centre
- NIH Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development
- NIH
- Grants-in-Aid for Scientific Research [26840011] Funding Source: KAKEN
- Medical Research Council [MC_PC_13029/2, MR/K000608/1B, G1001253, MC_PC_13029, MC_PC_13029/1, MR/K000608/1, G0601943, MC_U105663140, G0802760, G0601943B, MR/J004758/1, G108/638] Funding Source: researchfish
- National Institute for Health Research [CL-2013-17-005, NF-SI-0515-10082] Funding Source: researchfish
- MRC [MC_PC_13029/2, G0601943, G108/638, G1001253, MR/K000608/1, MC_PC_13029/1, G0802760, MC_U105663140, MR/J004758/1] Funding Source: UKRI
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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.
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