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

Proc. Natl. Acad. Sci. U.S.A.2016 Jul 26;113(30):E4276-85. Epub 2016 Jul 08
Gokhan Akman 1 , Radha Desai 1 , Laura J Bailey 2 , Takehiro Yasukawa 2 , Ilaria Dalla Rosa 1 , Romina Durigon 1 , J Bradley Holmes 3 , Chloe F Moss 1 , Mara Mennuni 1 , Henry Houlden 4 , Robert J Crouch 5 , Michael G Hanna 4 , Robert D S Pitceathly 6 , Antonella Spinazzola 7 , Ian J Holt 7
Gokhan Akman 1 , Radha Desai 1 , Laura J Bailey 2 , Takehiro Yasukawa 2 , Ilaria Dalla Rosa 1 , Romina Durigon 1 , J Bradley Holmes 3 , Chloe F Moss 1 , Mara Mennuni 1 , Henry Houlden 4 , Robert J Crouch 5 , Michael G Hanna 4 , Robert D S Pitceathly 6 , Antonella Spinazzola 7 , Ian J Holt 7
+ et al

[No authors listed]

Author information
  • 1 Medical Research Council, Mill Hill Laboratory, London NW7 1AA, United Kingdom;
  • 2 Medical Research Council Mitochondrial Biology Unit, Cambridge CB1 9SY, United Kingdom;
  • 3 Medical Research Council Mitochondrial Biology Unit, Cambridge CB1 9SY, United Kingdom; Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
  • 4 Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London WC1N 3BG, United Kingdom;
  • 5 Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
  • 6 Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London WC1N 3BG, United Kingdom; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
  • 7 Medical Research Council, Mill Hill Laboratory, London NW7 1AA, United Kingdom; ian.holt@headoffice.mrc.ac.uk Antonella.Spinazzola@crick.ac.uk.

摘要

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.

KEYWORDS: DNA segregation, R-loop, RNase H1, mitochondrial DNA, mitochondrial disease

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