TY - JOUR
T1 - Repair of pyrimidine(6-4)pyrimidone photoproducts in mouse skin
AU - Mitchell, David L.
AU - Cleaver, James E.
AU - Epstein, John H.
N1 - Funding Information:
uch of our knowledge concerning the mecha-nisms of phorocarcinogencsis and aging in human skin has been extrapolated from studies in mouse skin. Although mice have provided an invaluable M model system for analyzing many of the biologic parameters of skin cancer, they have not yielded much information regarding the initial molecular events responsible for tumorigenesis. In particular, the role of photodamage as lethal or mutagenic determinants in DNA has been difficult co ascertain because of the inability of mouse cells to remove cyclobutane pyrimidine dimers, the predominant lesions induced by ultraviolet (UV) light, by either photoreactivation (1 ,2] or excision repair (3,4]. Despite this repair deficiency, significant levels of unscheduled DNA synthesis (UDS) do occur in mouse skin irradiated in vivo [5,6]. In the past few years the pyrimidine(6-4)pyrimidone photoproduct, or (6-4) photoproduct, has been identified as an important lethal and mutagenic photoproduct [7,8). Analysis of mutations in specific DNA sequences has shown that the (6-4) photoproduct is probabl y the primary pre-mutagenic lesion induced by UV light in Manuscript received November 6, 1989; accepted for publication March 6, 1990. This research was supported in part by Dr. Mitchell's appoinnnent to the Alexander Hollaendcr Disunguished Postdoctoral Fellowship Program sponsored by the U.S. Department of Energy, Office of Health and Environmental Research, administered by the Oak Ridge Associated Universities, by NCI Grant CA 15605 and DOE contract D.E-AC03-76-SFOI 012. Reprint rcquens ro: Dr. David L. Mitchell, Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, CA 94143-0750. Abbreviations: CHO: Chinese hamster ovary MED: mlllimal erythemal dose RIA: radioimmunoassay UDS: unscheduled DNA synthesis UVB: ultraviolet B irradiation (290-320 nm} UVC: ultraviolet C irradiation (240-290 nm) XP: xeroderma pigmencosum
PY - 1990/7
Y1 - 1990/7
N2 - The induction and repair of cyclobutane pyrimidine dimers and pyrimidine(6-4)pyrimidone photoproducts in the epidermal DNA of ultraviolet-irradiated hairless mice were determined by radioimmunoassay. Few cyclobutane dimers were excised by 48 h after ultraviolet (UV) irradiation, whereas 50% of the (6-4) photoproducts were removed by 6 h, correlating with previously determined rates of unscheduled DNA synthesis in mouse skin. After this initial rapid phase of (6-4) photoproduct excision, a slower phase was observed between 6 and 48 h. These repair kinetics contrast with those for fibroblast cell cultures derived from mouse tissues irradiated with UV light yielding similar levels of damage. Although the initial rate of (6-4) photoproduct repair in cultured fibroblasts and epidermal cells was similar, the extent of repair in cultured cells was significantly greater, with most of the damage removed by 24 h. The kinetics for (6-4) photoproduct repair in mouse epidermal cells suggest that a significant population, such as terminally differentiated keratinocytes, may have a reduced repair capacity and that the culture process may select for more rapidly proliferating, repair-proficient stem cells.
AB - The induction and repair of cyclobutane pyrimidine dimers and pyrimidine(6-4)pyrimidone photoproducts in the epidermal DNA of ultraviolet-irradiated hairless mice were determined by radioimmunoassay. Few cyclobutane dimers were excised by 48 h after ultraviolet (UV) irradiation, whereas 50% of the (6-4) photoproducts were removed by 6 h, correlating with previously determined rates of unscheduled DNA synthesis in mouse skin. After this initial rapid phase of (6-4) photoproduct excision, a slower phase was observed between 6 and 48 h. These repair kinetics contrast with those for fibroblast cell cultures derived from mouse tissues irradiated with UV light yielding similar levels of damage. Although the initial rate of (6-4) photoproduct repair in cultured fibroblasts and epidermal cells was similar, the extent of repair in cultured cells was significantly greater, with most of the damage removed by 24 h. The kinetics for (6-4) photoproduct repair in mouse epidermal cells suggest that a significant population, such as terminally differentiated keratinocytes, may have a reduced repair capacity and that the culture process may select for more rapidly proliferating, repair-proficient stem cells.
UR - https://www.scopus.com/pages/publications/0025315988
UR - https://www.scopus.com/pages/publications/0025315988#tab=citedBy
U2 - 10.1111/1523-1747.ep12873312
DO - 10.1111/1523-1747.ep12873312
M3 - Article
C2 - 2366001
AN - SCOPUS:0025315988
SN - 0022-202X
VL - 95
SP - 55
EP - 59
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 1
ER -