期刊
NUCLEIC ACIDS RESEARCH
卷 50, 期 2, 页码 989-999出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab1251
关键词
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资金
- Swedish Research Council [2018-02439, 201701257]
- IngaBritt and Arne Lundberg's Research Foundation
- Swedish Cancer Foundation
- Knut and Alice Wallenberg Foundation
- European Research Council [2016-683191]
- Swedish government [ALFGBG-727491, ALFGBG-728151]
- Swedish Research Council
This study demonstrates that misincorporated ribonucleotides (rNMPs) in human mitochondrial genome can affect mitochondrial transcription, especially when they are present in consecutive stretches. This finding suggests that impaired transcription may be associated with genetic disorders characterized by imbalanced nucleotide pools and higher levels of embedded rNMPs.
Human mitochondria lack ribonucleotide excision repair pathways, causing misincorporated ribonucleotides (rNMPs) to remain embedded in the mitochondrial genome. Previous studies have demonstrated that human mitochondrial DNA polymerase gamma can bypass a single rNMP, but that longer stretches of rNMPs present an obstacle to mitochondrial DNA replication. Whether embedded rNMPs also affect mitochondrial transcription has not been addressed. Here we demonstrate that mitochondrial RNA polymerase elongation activity is affected by a single, embedded rNMP in the template strand. The effect is aggravated at stretches with two or more consecutive rNMPs in a row and cannot be overcome by addition of the mitochondrial transcription elongation factor TEFM. Our findings lead us to suggest that impaired transcription may be of functional relevance in genetic disorders associated with imbalanced nucleotide pools and higher levels of embedded rNMPs.
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