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

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 30 Pg. E4276-85 (07 26 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27402764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Ribonuclease H
• ribonuclease HI

Topics

• Animals
• Cell Line, Tumor
• Cells, Cultured
• DNA Replication
• DNA, Mitochondrial (chemistry, genetics, metabolism)
• Female
• HEK293 Cells
• Humans
• Male
• Mice
• Mitochondria (genetics, metabolism)
• Mitochondrial Diseases (genetics, metabolism)
• Mutation
• Nucleic Acid Conformation
• Ribonuclease H (genetics, metabolism)