Elimination of rNMPs from mitochondrial DNA has no effect on its stability

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 25; pp. 14306 - 14313
• Main Authors: Wanrooij, Paulina H., Tran, Phong, Thompson, Liam J., Carvalho, Gustavo, Sharma, Sushma, Kreisel, Katrin, Navarrete, Clara, Feldberg, Anna-Lena, Watt, Danielle L., Nilsson, Anna Karin, Engqvist, Martin K. M., Clausen, Anders R., Chabes, Andrei
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.06.2020
• Subjects: Animals; Biological Sciences; Copy number; deoxynucleotide pools; Deoxyribonucleic acid; discrimination; DNA; DNA Damage; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; dNTP pool; Female; Gene Dosage; Genomes; Genomic Instability - physiology; hiv-1 infection; in-vivo; Life span; Male; Medical Biotechnology; Medicinsk bioteknologi; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial DNA; mtDNA; mutations; Nucleotides; polymerase; ribonucleotide incorporation; Ribonucleotides; Ribonucleotides - genetics; Ribonucleotides - metabolism; rnase; SAM Domain and HD Domain-Containing Protein 1 - genetics; SAMHD1; Science & Technology - Other Topics; Stability; ribonucleotide incorporation; dNTP pool; SAMHD1; mtDNA; mitochondrial DNA
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1916851117

Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to genome stability and can result in DNA strand breaks when not removed in a timely manner. However, the presence of a certain level of rNMPs is tolerated in mitochondrial DNA (mtDNA) although aberrant mtDNA rNMP content has been identified in disease models. We investigated the effect of incorporated rNMPs on mtDNA stability over the mouse life span and found that the mtDNA rNMP content increased during early life. The rNMP content of mtDNA varied greatly across different tissues and was defined by the rNTP/dNTP ratio of the tissue. Accordingly, mtDNA rNMPs were nearly absent in SAMHD1 −/− mice that have increased dNTP pools. The near absence of rNMPs did not, however, appreciably affect mtDNA copy number or the levels of mtDNA molecules with deletions or strand breaks in aged animals near the end of their life span. The physiological rNMP load therefore does not contribute to the progressive loss of mtDNA quality that occurs as mice age.