Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging
Defects in the DNA repair mechanism nucleotide excision repair (NER) may lead to tumors in xeroderma pigmentosum (XP) or to premature aging with loss of subcutaneous fat in Cockayne syndrome (CS). Mutations of mitochondrial (mt)DNA play a role in aging, but a link between the NER-associated CS proteins and base excision repair (BER)-associated proteins in mitochondrial aging remains enigmatic. We show functional increase of CSA and CSB inside mt and complex formation with mtDNA, mt human 8-oxoguanine glycosylase (mtOGG)-1, and mt single-stranded DNA binding protein (mtSSBP)-1 upon oxidative stress. MtDNA mutations are highly increased in cells from CS patients and in subcutaneous fat of aged Csbm/m and Csa-/- mice. Thus, the NER-proteins CSA and CSB localize to mt and directly interact with BER-associated human mitochondrial 8-oxoguanine glycosylase-1 to protect from aging- and stress-induced mtDNA mutations and apoptosis-mediated loss of subcutaneous fat, a hallmark of aging found in animal models, human progeroid syndromes like CS and in normal human aging.
|Keywords||8 hydroxyguanine, Cockayne syndrome, DNA repair, adolescent, aged, animal cell, animal tissue, apoptosis, article, excision repair, human, human cell, michondrial single stranded DNA binding protein 1, mitochondrial 8 oxoguanine glycosylase 1, mitochondrial DNA, mitochondrion, mouse, nonhuman, oxidative stress, premature aging, priority journal, protein localization, single stranded DNA binding protein, subcutaneous fat, unclassified drug, xeroderma pigmentosum|
|Persistent URL||dx.doi.org/10.1084/jem.20091834, hdl.handle.net/1765/19957|
|Journal||The Journal of Experimental Medicine|
Kamenisch, Y, Fousteri, M.I, Knoch, J, Von Thaler, A.K, Fehrenbacher, B, Kato, H, … Berneburg, M. (2010). Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging. The Journal of Experimental Medicine, 207(2), 379–390. doi:10.1084/jem.20091834