Mechanisms and implications of the age-associated decrease in DNA repair capacity.
Skin cancer incidence is clearly linked to UV irradiation and increases exponentially with age. We studied the rate of removal of thymine dimers and (6-4) photoproducts in UV-irradiated human dermal fibroblasts derived from donors of different ages. There was a significant decrease with aging in the repair rates of both thymine dimers and (6-4) photoproducts (P<0.001). In addition, there was an age-associated decrease in the protein levels of ERCC3, PCNA, RPA, XPA, and p53 that participate in nucleotide excision repair. Moreover, the mRNA levels of XPA, ERCC3, and PCNA were significantly reduced with aging, suggesting that these decreases are often regulated at the mRNA level. Furthermore, with age induction of p53 after UV irradiation was significantly reduced. Taken together, our data suggest that the age-associated decrease in the repair of UV-induced DNA damage results at least in part from decreased levels of proteins that participate in the repair process.
Goukassian
D
D
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Gad
F
F
Yaar
M
M
Eller
M S
MS
Nehal
U S
US
Gilchrest
B A
BA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000528:radiation effects; D029721:Drosophila Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011740:Pyrimidine Dimers / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051716:Replication Protein A; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D015595:Skin Aging / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018809:Proliferating Cell Nuclear Antigen; D011740:Pyrimidine Dimers; D012333:RNA, Messenger; C497167:RPA1 protein, human; D051716:Replication Protein A; D016159:Tumor Suppressor Protein p53; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C078672:hay protein, Drosophila