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Lookup NU author(s): Dr Jim StewartORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Somatic mutations in the nuclear genome are required for tumor formation, but the functional consequences of somatic mitochondrial DNA (mtDNA) mutations are less understood. Here we identify somatic mtDNA mutations across 527 tumors and 14 cancer types, using an approach that takes advantage of evidence from both genomic and transcriptomic sequencing. We find that there is selective pressure against deleterious coding mutations, supporting that functional mitochondria are required in tumor cells, and also observe a strong mutational strand bias, compatible with endogenous replication-coupled errors as the major source of mutations. Interestingly, while allelic ratios in general were consistent in RNA compared to DNA, some mutations in tRNAs displayed strong allelic imbalances caused by accumulation of unprocessed tRNA precursors. The effect was explained by altered secondary structure, demonstrating that correct tRNA folding is a major determinant for processing of polycistronic mitochondrial transcripts. Additionally, the data suggest that tRNA clusters are preferably processed in the 3′ to 5′ direction. Our study gives insights into mtDNA function in cancer and answers questions regarding mitochondrial tRNA biogenesis that are difficult to address in controlled experimental systems.
Author(s): Stewart JB, Alaei-Mahabadi B, Sabarinathan R, Samuelsson T, Gorodkin J, Gustafsson CM, Larsson E
Publication type: Article
Publication status: Published
Journal: PLoS Genetics
Year: 2015
Volume: 11
Issue: 3
Online publication date: 30/06/2015
Acceptance date: 03/06/2015
Date deposited: 21/12/2020
ISSN (print): 1553-7390
ISSN (electronic): 1553-7404
Publisher: Public Library of Science
URL: https://doi.org/10.1371/journal.pgen.1005333
DOI: 10.1371/journal.pgen.1005333
PubMed id: 26125550
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