eprintid: 10025004 rev_number: 53 eprint_status: archive userid: 608 dir: disk0/10/02/50/04 datestamp: 2017-11-02 15:24:42 lastmod: 2021-09-20 22:19:36 status_changed: 2017-11-02 15:24:42 type: article metadata_visibility: show creators_name: holt, IJ creators_name: Dalla Rosa, I creators_name: Spinazzola, A title: Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F84 divisions: C08 note: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 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. date: 2017-12-15 date_type: published publisher: Oxford University Press official_url: http://dx.doi.org/10.1093/nar/gkx1009 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1444804 doi: 10.1093/nar/gkx1009 lyricists_name: Dalla Rosa, Ilaria lyricists_name: Holt, Ian lyricists_name: Jones, Aleck lyricists_name: Moss, Chloe lyricists_name: Spinazzola, Antonella lyricists_id: IDROS74 lyricists_id: IJHOL01 lyricists_id: AWEJO85 lyricists_id: CMOSS34 lyricists_id: ASPIN93 actors_name: Dewerpe, Marie actors_id: MDDEW97 actors_role: owner full_text_status: public publication: Nucleic Acids Research volume: 45 number: 22 pagerange: 12808-12815 issn: 0305-1048 citation: holt, IJ; Dalla Rosa, I; Spinazzola, A; (2017) Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model. Nucleic Acids Research , 45 (22) pp. 12808-12815. 10.1093/nar/gkx1009 <https://doi.org/10.1093/nar%2Fgkx1009>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10025004/1/Dalla%20Rosa_gkx1009.pdf