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

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. Green open access

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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.

Type: Article
Title: Pathological ribonuclease H1 causes R-loop depletion and aberrant DNA segregation in mitochondria
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1600537113
Publisher version: http://doi.org/10.1073/pnas.1600537113
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, RNase H1, R-loop, mitochondrial DNA, DNA segregation, mitochondrial disease, IMPAIR MTDNA REPLICATION, LIGHT-STRAND PROMOTER, ACCESSORY SUBUNIT, DISPLACEMENT LOOP, ORIGIN, MUTATIONS, REGION, MAINTENANCE, DELETIONS, NUCLEOIDS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/1506125
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