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

Artikel i vetenskaplig tidskrift
Författare Anna-Karin Berglund
Clara Navarrete
Martin K M Engqvist
Emily Hoberg
Zsolt Szilagyi
Robert W Taylor
Claes M Gustafsson
Maria Falkenberg
Anders R Clausen
Publicerad i PLoS genetics
Volym 13
Nummer/häfte 2
ISSN 1553-7404
Publiceringsår 2017
Publicerad vid Institutionen för biomedicin
Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Språk en
Länkar dx.doi.org/10.1371/journal.pgen.100...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Molekylärbiologi, Molekylärbiologi, Genetik, Bioinformatik och systembiologi

Sammanfattning

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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