Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging

J Exp Med. 2010 Feb 15;207(2):379-90. doi: 10.1084/jem.20091834. Epub 2010 Jan 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging / metabolism
  • Animals
  • Apoptosis
  • Cockayne Syndrome / genetics*
  • Cockayne Syndrome / metabolism
  • Cockayne Syndrome / physiopathology
  • DNA Glycosylases / metabolism
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • DNA Repair*
  • DNA, Mitochondrial / genetics*
  • DNA-Binding Proteins
  • Humans
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Oxidative Stress
  • Poly-ADP-Ribose Binding Proteins
  • Protein Binding
  • Proteins / genetics
  • Proteins / metabolism
  • Subcutaneous Fat / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Ckn1 protein, mouse
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • ERCC8 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Proteins
  • Transcription Factors
  • DNA Glycosylases
  • Ogg1 protein, mouse
  • oxoguanine glycosylase 1, human
  • DNA Helicases
  • ERCC6 protein, human
  • Ercc6 protein, mouse
  • DNA Repair Enzymes