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.

[1]  R. Paus,et al.  Profiling the response of human hair follicles to ultraviolet radiation. , 2009, The Journal of investigative dermatology.

[2]  Ruth Halsne,et al.  Accumulation of mitochondrial DNA damage and bioenergetic dysfunction in CSB defective cells , 2009, The FEBS journal.

[3]  P. Hanawalt,et al.  A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage , 2009, Proceedings of the National Academy of Sciences.

[4]  V. Bohr,et al.  Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase* , 2009, Journal of Biological Chemistry.

[5]  R. Aurora,et al.  Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release. , 2008, Rejuvenation research.

[6]  V. Bohr,et al.  The role of Cockayne Syndrome group B (CSB) protein in base excision repair and aging , 2008, Mechanisms of Ageing and Development.

[7]  B. Epe,et al.  The basal levels of 8-oxoG and other oxidative modifications in intact mitochondrial DNA are low even in repair-deficient (Ogg1(-/-)/Csb(-/-)) mice. , 2007, Mutation research.

[8]  I Iavarone,et al.  The role of CSA in the response to oxidative DNA damage in human cells , 2007, Oncogene.

[9]  L. Mullenders,et al.  Nucleotide excision repair in differentiated cells. , 2007, Mutation research.

[10]  M. Beal,et al.  Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases , 2006, Nature.

[11]  N. Pfanner,et al.  Toward the complete yeast mitochondrial proteome: multidimensional separation techniques for mitochondrial proteomics. , 2006, Journal of proteome research.

[12]  C. Geula,et al.  Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons , 2006, Nature Genetics.

[13]  A. Sarasin,et al.  Transcription-Coupled Repair of 8-oxoguanine: Requirement for XPG, TFIIH, and CSB and Implications for Cockayne Syndrome , 2005, Cell.

[14]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[15]  L. Declercq,et al.  Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences. , 2005, The Journal of investigative dermatology.

[16]  M. Schirle,et al.  Bartonella Adhesin A Mediates a Proangiogenic Host Cell Response , 2004, The Journal of experimental medicine.

[17]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[18]  Annette Pfahlberg,et al.  Induction of the photoaging-associated mitochondrial common deletion in vivo in normal human skin. , 2004, The Journal of investigative dermatology.

[19]  A. Martinuzzi,et al.  Apoptotic Cell Death of Cybrid Cells Bearing Leber's Hereditary Optic Neuropathy Mutations Is Caspase Independent , 2003, Annals of the New York Academy of Sciences.

[20]  L. Mullenders,et al.  Nucleotide excision repair and its interplay with transcription. , 2003, Toxicology.

[21]  F. Hanaoka,et al.  The comings and goings of nucleotide excision repair factors on damaged DNA , 2003, The EMBO journal.

[22]  V. Bohr,et al.  Mammalian 8-Oxoguanine DNA Glycosylase 1 Incises 8-Oxoadenine Opposite Cytosine in Nuclei and Mitochondria, while a Different Glycosylase Incises 8-Oxoadenine Opposite Guanine in Nuclei* , 2003, Journal of Biological Chemistry.

[23]  K. J. Krishnan,et al.  Mitochondrial DNA damage in non-melanoma skin cancer , 2003, British Journal of Cancer.

[24]  J. Stone,et al.  Mitochondrial deletions in normal and degenerating rat retina. , 2003, Advances in experimental medicine and biology.

[25]  V. Bohr,et al.  Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B , 2002, Oncogene.

[26]  Y. Pommier,et al.  Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. , 2002, Cancer research.

[27]  S. Velasco-Miguel,et al.  UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice. , 2002, DNA repair.

[28]  J. Hoeijmakers,et al.  Translocation of Cockayne syndrome group A protein to the nuclear matrix: Possible relevance to transcription-coupled DNA repair , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Müftüoğlu,et al.  The Cockayne Syndrome Group B Gene Product Is Involved in General Genome Base Excision Repair of 8-Hydroxyguanine in DNA* , 2001, The Journal of Biological Chemistry.

[30]  K. Wittern,et al.  In human keratinocytes the Common Deletion reflects donor variabilities rather than chronologic aging and can be induced by ultraviolet A irradiation. , 2001, The Journal of investigative dermatology.

[31]  E. Seeberg,et al.  Repair of 8-oxodeoxyguanosine lesions in mitochondrial dna depends on the oxoguanine dna glycosylase (OGG1) gene and 8-oxoguanine accumulates in the mitochondrial dna of OGG1-defective mice. , 2001, Cancer research.

[32]  D. Bogenhagen,et al.  Enzymology of mitochondrial base excision repair. , 2001, Progress in nucleic acid research and molecular biology.

[33]  A. Lehmann,et al.  Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription. , 2001, Advances in genetics.

[34]  V. Bohr,et al.  Oxidative damage-induced PCNA complex formation is efficient in xeroderma pigmentosum group A but reduced in Cockayne syndrome group B cells. , 1999, Nucleic acids research.

[35]  T. Ruzicka,et al.  Singlet Oxygen Mediates the UVA-induced Generation of the Photoaging-associated Mitochondrial Common Deletion* , 1999, The Journal of Biological Chemistry.

[36]  Y. Nakabeppu,et al.  Expression and differential intracellular localization of two major forms of human 8-oxoguanine DNA glycosylase encoded by alternatively spliced OGG1 mRNAs. , 1999, Molecular biology of the cell.

[37]  H. van Steeg,et al.  Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. , 1999, Molecular medicine today.

[38]  E. Dogliotti,et al.  DNA repair of UV photoproducts and mutagenesis in human mitochondrial DNA. , 1997, Journal of molecular biology.

[39]  T. Ruzicka,et al.  Chronically Ultraviolet‐exposed Human Skin Shows a Higher Mutation Frequency of Mitochondrial DNA as Compared to Unexposed Skin and the Hematopoietic System , 1997, Photochemistry and photobiology.

[40]  P. Laipis,et al.  Multiple Deletions Are Detectable in Mitochondrial DNA of Aging Mice (*) , 1995, The Journal of Biological Chemistry.

[41]  A. Lehmann.  Nucleotide excision repair and the link with transcription. , 1995, Trends in biochemical sciences.

[42]  H. C. Lee,et al.  Human skin mitochondrial DNA deletions associated with light exposure. , 1994, Archives of biochemistry and biophysics.

[43]  V. Bohr,et al.  Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. , 1992, Carcinogenesis.

[44]  M. Nance,et al.  Cockayne syndrome: review of 140 cases. , 1992, American journal of medical genetics.

[45]  R. Wood.  Repair of pyrimidine dimer ultraviolet light photoproducts by human cell extracts. , 1989, Biochemistry.

[46]  M. Eilers,et al.  Import of proteins into mitochondria. , 1988, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[47]  D. A. Clayton,et al.  The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. , 1974, Proceedings of the National Academy of Sciences of the United States of America.