Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model

Chloe F. Moss, Ilaria Dalla Rosa, Lilian E. Hunt, Takehiro Yasukawa, Robert Young, Aleck W.E. Jones, Kaalak Reddy, Radha Desai, Sam Virtue, Greg Elgar, Peter Voshol, Martin S. Taylor, Ian J. Holt, Martin A.M. Reijns, Antonella Spinazzola

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

All DNA polymerases misincorporate ribonucleotides despite their preference for deoxyribonucleotides, and analysis of cultured cells indicates that mammalian mitochondrial DNA (mtDNA) tolerates such replication errors. However, it is not clear to what extent misincorporation occurs in tissues, or whether this plays a role in human disease. Here, we show that mtDNA of solid tissues contains many more embedded ribonucleotides than that of cultured cells, consistent with the high ratio of ribonucleotide to deoxynucleotide triphosphates in tissues, and that riboadenosines account for three-quarters of them. The pattern of embedded ribonucleotides changes in a mouse model of Mpv17 deficiency, which displays a marked increase in rGMPs in mtDNA. However, while the mitochondrial dGTP is low in the Mpv17-/- liver, the brain shows no change in the overall dGTP pool, leading us to suggest that Mpv17 determines the local concentration or quality of dGTP. Embedded rGMPs are expected to distort the mtDNA and impede its replication, and elevated rGMP incorporation is associated with early-onset mtDNA depletion in liver and late-onset multiple deletions in brain of Mpv17-/- mice. These findings suggest aberrant ribonucleotide incorporation is a primary mtDNA abnormality that can result in pathology.

Original languageEnglish
Pages (from-to)12808-12815
Number of pages8
JournalNucleic acids research
Volume45
Issue number22
DOIs
Publication statusPublished - Dec 15 2017

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Ribonucleotides
Mitochondrial DNA
Cultured Cells
Deoxyribonucleotides
Liver
Brain
DNA-Directed DNA Polymerase
Pathology
deoxyguanosine triphosphate

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model. / Moss, Chloe F.; Rosa, Ilaria Dalla; Hunt, Lilian E.; Yasukawa, Takehiro; Young, Robert; Jones, Aleck W.E.; Reddy, Kaalak; Desai, Radha; Virtue, Sam; Elgar, Greg; Voshol, Peter; Taylor, Martin S.; Holt, Ian J.; Reijns, Martin A.M.; Spinazzola, Antonella.

In: Nucleic acids research, Vol. 45, No. 22, 15.12.2017, p. 12808-12815.

Research output: Contribution to journalArticle

Moss, CF, Rosa, ID, Hunt, LE, Yasukawa, T, Young, R, Jones, AWE, Reddy, K, Desai, R, Virtue, S, Elgar, G, Voshol, P, Taylor, MS, Holt, IJ, Reijns, MAM & Spinazzola, A 2017, 'Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model', Nucleic acids research, vol. 45, no. 22, pp. 12808-12815. https://doi.org/10.1093/nar/gkx1009
Moss, Chloe F. ; Rosa, Ilaria Dalla ; Hunt, Lilian E. ; Yasukawa, Takehiro ; Young, Robert ; Jones, Aleck W.E. ; Reddy, Kaalak ; Desai, Radha ; Virtue, Sam ; Elgar, Greg ; Voshol, Peter ; Taylor, Martin S. ; Holt, Ian J. ; Reijns, Martin A.M. ; Spinazzola, Antonella. / Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model. In: Nucleic acids research. 2017 ; Vol. 45, No. 22. pp. 12808-12815.
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