Akman, G;
Desai, R;
Bailey, LJ;
Yasukawa, T;
Rosa, ID;
Durigon, R;
Holmes, JB;
... Holt, IJ; + view all
(2016)
Pathological ribonuclease H1 causes R-loop depletion and aberrant DNA segregation in mitochondria.
Proceedings of The National Academy of Sciences of The United States of America (PNAS)
, 113
(30)
E4276-E4285.
10.1073/pnas.1600537113.
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Abstract
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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