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Nucleotide pools dictate the identity and frequency of ribonucleotide incorporation in mitochondrial DNA.

Journal article
Authors Anna-Karin Berglund
Clara Navarrete
Martin K M Engqvist
Emily Hoberg
Zsolt Szilagyi
Robert W Taylor
Claes M Gustafsson
Maria Falkenberg
Anders R Clausen
Published in PLoS genetics
Volume 13
Issue 2
ISSN 1553-7404
Publication year 2017
Published at Institute of Biomedicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Language en
Links dx.doi.org/10.1371/journal.pgen.100...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Molecular biology, Molecular biology, Genetics, Bioinformatics and Systems Biology

Abstract

Previous work has demonstrated the presence of ribonucleotides in human mitochondrial DNA (mtDNA) and in the present study we use a genome-wide approach to precisely map the location of these. We find that ribonucleotides are distributed evenly between the heavy- and light-strand of mtDNA. The relative levels of incorporated ribonucleotides reflect that DNA polymerase γ discriminates the four ribonucleotides differentially during DNA synthesis. The observed pattern is also dependent on the mitochondrial deoxyribonucleotide (dNTP) pools and disease-causing mutations that change these pools alter both the absolute and relative levels of incorporated ribonucleotides. Our analyses strongly suggest that DNA polymerase γ-dependent incorporation is the main source of ribonucleotides in mtDNA and argues against the existence of a mitochondrial ribonucleotide excision repair pathway in human cells. Furthermore, we clearly demonstrate that when dNTP pools are limiting, ribonucleotides serve as a source of building blocks to maintain DNA replication. Increased levels of embedded ribonucleotides in patient cells with disturbed nucleotide pools may contribute to a pathogenic mechanism that affects mtDNA stability and impair new rounds of mtDNA replication.

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