TY - JOUR
T1 - Pathological ribonuclease H1 causes R-loop depletion and aberrant DNA segregation in mitochondria
AU - Akman, Gokhan
AU - Desai, Radha
AU - Bailey, Laura J.
AU - Yasukawa, Takehiro
AU - Rosa, Ilaria Dalla
AU - Durigon, Romina
AU - Holmes, J. Bradley
AU - Moss, Chloe F.
AU - Mennuni, Mara
AU - Houlden, Henry
AU - Crouch, Robert J.
AU - Hanna, Michael G.
AU - Pitceathly, Robert D.S.
AU - Spinazzola, Antonella
AU - Holt, Ian J.
N1 - Funding Information:
J.B.H. was an NIH-CamGrad Scholar (2006-2010). M.M. is supported by the European Commission, MEET Project Grant 317433. The study was funded by a Medical Research Council (MRC) Intramural Award (to I.J.H.) and MRC Senior Non-Clinical Fellowship MC- PC- 13029 (to A.S.). R.D.S.P., H.H., and M.G.H. are supported by MRC Centre for Neuromuscular Diseases Grant G0601943, the UK National Health Service Specialised Service for Rare Mitochondrial Diseases of Adults and Children, and the National Institute for Health Research University College London Hospitals/University College London Biomedical Research Centre. R.J.C. is supported by the NIH Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
PY - 2016/7/26
Y1 - 2016/7/26
N2 - 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.
AB - 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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U2 - 10.1073/pnas.1600537113
DO - 10.1073/pnas.1600537113
M3 - Article
C2 - 27402764
AN - SCOPUS:84979539098
SN - 0027-8424
VL - 113
SP - E4276-E4285
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -