期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 207, 期 2, 页码 379-390出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20091834
关键词
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资金
- Deutsche Forschungsgemeinschaft [Be 2005/2-1, 2-2, 2-3, KFO 142 Be 2005/3-1, 3-2, SFB 728, GK 1033, FP6-512113, Sch897/3, SFB 773, SFB 685]
- BMBF [0315409B]
- NIDCR [R01 DE017514-01]
- Wilhelm Sander-Stiftung [205.043.2]
- Desutsche Krebshilfe [107128]
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 Csb(m/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.
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