The base excision repair pathway is initiated by the action of a class of enzymes known as DNA glycosylases, which recognize and release the damaged base, and thus give specificity to the repair process. Mammalian cells carry two major DNA glycosylases for the repair of oxidized bases, oxoguanine DNA glycosylase (OGG1) and Endonuclease III homologue (NTH1). We found that OGG1 plays a crucial role in the repair of oxidized lesions in mitochondria and is probably the only DNA glycosylase for 8-oxoG removal in these organelles. In human cells two distinct OGG1 isoforms are expressed, alpha and beta. All BER enzymes are encoded in the nucleus and transported to mitochondria;however there is very limited information on the regulation of mitochondrial BER. In mammalian mitochondria the mtDNA is found in a large protein-DNA complex known as the nucleoid. One of the most abundant protein components of mammalian nucleoids is the transcription factor TFAM, which has been postulated to have a structural function in compacting mtDNA into the nucleoid structure. Using recombinant human TFAM, we investigated whether TFAM could modulate mtDNA repair. We found that TFAM could inhibit BER proteins and mitochondrial pol gamma. We proposed that TFAM may be functioning like nuclear histones and therefore proposed that a TFAM remodeling protein must exit in mitochondria to allow for mtDNA metabolism. We went on to show that p53, a known TFAM interacting protein, could relieve TFAM inhibition of OGG1 incision. In separate studies, we documented that RECQL4 and CSB were present in mitochondria, thus we evaluated if each protein could relieve TFAM inhibition. We observed CSB, but not RECQL4, could display TFAM and alleviate its inhibition. We are continuing to search for and interrogate protein-interaction with TFAM in an attempt to more fully characterize mtDNA repair and metabolism. Another important protein involved in mitochondrial DNA metabolism is the helicase SUV3. We have investigated the biochemical functions of SUV3, and it appears to interact with some mitochondrial and telomere proteins, making it possible that it functions both at telomeres and in mitochondria. This is under further investigation.
Baptiste, Beverly A; Katchur, Steven R; Fivenson, Elayne M et al. (2018) Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention. Free Radic Biol Med 124:149-162 |
Mitchell, Sarah J; Bernier, Michel; Aon, Miguel A et al. (2018) Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice. Cell Metab 27:667-676.e4 |
Sykora, P; Kanno, S; Akbari, M et al. (2017) DNA polymerase beta participates in mitochondrial DNA repair. Mol Cell Biol : |
Hegde, Muralidhar L; Bohr, Vilhelm A; Mitra, Sankar (2017) DNA damage responses in central nervous system and age-associated neurodegeneration. Mech Ageing Dev 161:1-3 |
Fang, Evandro F; Waltz, Tyler B; Kassahun, Henok et al. (2017) Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci Rep 7:46208 |
Fivenson, Elayne M; Lautrup, Sofie; Sun, Nuo et al. (2017) Mitophagy in neurodegeneration and aging. Neurochem Int 109:202-209 |
Kerr, Jesse S; Adriaanse, Bryan A; Greig, Nigel H et al. (2017) Mitophagy and Alzheimer's Disease: Cellular and Molecular Mechanisms. Trends Neurosci 40:151-166 |
Fang, Evandro F; Lautrup, Sofie; Hou, Yujun et al. (2017) NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med 23:899-916 |
Fang, Evandro F; Bohr, Vilhelm A (2017) NAD(+): The convergence of DNA repair and mitophagy. Autophagy 13:442-443 |
Fakouri, Nima Borhan; Durhuus, Jon Ambæk; Regnell, Christine Elisabeth et al. (2017) Rev1 contributes to proper mitochondrial function via the PARP-NAD+-SIRT1-PGC1? axis. Sci Rep 7:12480 |
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