Radiation Xeroderma pigmentosum

Cleaver, J.E., DNA repair with purines and pyrimidines in radiation- and carcinogen-damaged normal and Xeroderma pigmentosum human cells, Cancer Res., 33, 362,1972. 

Thymine dimers (Gj) UV radiation Excision endonuclease (deficient in Xeroderma pigmentosum) DNA polymerase DNA ligase... 

The deficiency of an excision endonuclease may produce an exquisite sensitivity to ultraviolet radiation in Xeroderma pigmentosum. Which of the following functions would be absent in a patient deficient in this endonuclease ... 

The specific interaction of chemicals or radiation with DNA activate cdlular DNA repair processes which appear to play an important role in carcinogenesis. Eukaryotic cells show enhanced repair capacity for repair of viral nucleic add if the host cells are first damaged by chemicals or irradiation. The ihanced susceptibility to cancer of patients with defective repair systems, such as those with xeroderma pigmentosum, suggests that intact repair mechanisms are protective... 

Peak, J.G, Pilas, B., Dudek, E.J. Peak, M.J. (1991) DNA breaks caused by monochromatic 365 nm ultraviolet-A radiation or hydrogen peroxide and their repair in human epithelioid and xeroderma pigmentosum cells. Photochem. Photobiol., 54, 197-203... 

For example, persons with xeroderma pigmentosum are deficient in enzymes that repair DNA damage done by ultraviolet radiation, and they develop skin tumors on areas of the body exposed to sunlight. For their own protection, they should not be farmers, cowboys, or lifeguards on sunny beaches. Some chemicals mimic ultraviolet radiation in their effects on DNA, and such persons are expected to be especially susceptible to them. 

Ultraviolet light produces pyrimidine dimers in human DNA, as it does in E. coli DNA. Furthermore, the repair mechanisms are similar. Studies of skin fibroblasts from patients with xeroderma pigmentosum have revealed a biochemical defect in one form of this disease. In normal fibro-blasts, half the pyrimidine dimers produced by ultraviolet radiation are excised in less than 24 hours. In contrast, almost no dimers are excised in this time interval in fibroblasts derived from patients with xeroderma pigmentosum. The results of these studies show that xeroderma pigmentosum can be produced by a defect in the excinuclease that hydrolyzes the DNA backbone near a pyrimidine dimer. The drastic clinical consequences of this enzymatic defect emphasize the critical importance of DNA-repair processes. The disease can also be caused by mutations in eight other genes for DNA repair, which attests to the complexity of repair processes. 

The answer is e. (Murray, pp 412-434. Scriver, pp 677-704. Sack, pp 3-29. Wilson, pp 99-121.) Xeroderma pigmentosum (278700) appears to be due to the inability of an excision-repair system to remove thymine dimers, which are formed on exposure of DNA to ultraviolet radiation. This results in a deficiency in the ability to repair the damaged DNA. Mutagenesis by this mechanism is presumably the basis for the multiple neoplasms that occur in patients who have this disease. 

Exposure to UV radiation from sunlight is the major cause of human skin cancer. Skin tumors from patients with Xeroderma pigmentosum, a DNA-repair deficiency associated with increased sensitivity to UV, show a particularly high frequency of these CC to TT transitions (Dumaz et al., 1993). Mutations at dipyrimidines have been observed in the normal skin of sun-exposed skin cancer patients (Jonason et al., 1996 Nakazawa et al., 1994 Ren et al., 1996a). The localization of mutations in skin shows striking differences with other types of cancers, with hotspots at codons 177-179 and... 

Response to UVC Radiation and Bz. Similar features of the cellular response were examined after UVC + Bz treatm t as in the case of X or y rays + Bz (5). The results are summarized in Table 2. In contrast with LY-R cells and numerous other cell lines, LY-S cells were sensitized to UVC radiation by Bz. As in the case of X or y + Bz treatment, die distinct features of LY-S cell response to UVC + Bz treatment can be explained by low ligase I activity and hence, the necessity to activate ligase n. In LY-R cells, as in xeroderma pigmentosum cells (15), the rate of DNA incisions seems too low to activate poly(ADP-ribose) polymerase. On the other hand, LY-R cells may synthesize NAD+ more efficiently than LY-S cells (Table 1), and be able to maintain a stable NAD+ level in spite of poly(ADP-ribose) polymerase activation. In fact, when a double-labelling modification of the DNA unwinding method was used to examine the difference in sb frequency between Bz-treated and untreated UVC irradiated cells, the results were identical for LY-R and LY-S cells. We interpreted this as an indication of a Bz-sensitive base excision repair system (16,17) operating in both cell strains (in contrast with a nucleotide excision functional only in LY-S strain). Lack of nucleotide excision presumably makes LY-R cells sufficiently sensitive to UVC radiation that the base excision repair is not limiting for survival. 

A notorious photochemical olefin dimerization occurs on exposure of DN A to UV radiation. The primary event involves the dimerization of adjacent thymine (T) residues to produce the thymine dimer shown. Needless to say, this is not a favorable event for a living system, and extensive repair systems involving enzymes termed photolyases exist to excise the dimer and repair the DNA lesion. If not adequately repaired, however, such thymine dimers can lead to cell death (our skin peels when we get a sunburn) or can convert a healthy cell into a cancer cell. An inherited disorder involving defects in the repair system can lead to xeroderma pigmentosum, which involves hypersensitivity to UV irradiation and increased risk of skin cancer. An interesting consequence of this photochemistry is that species that live at very high altitudes,... 

Keyse, S.M., Moss, S.H., and Davies, K.J.G., Action spectra for inactivation of normal and Xeroderma pigmentosum human skin fibroblasts by ultraviolet radiations, Photochem. PhotobioL, 37, 307,1983. Jagger, J., Solar-UV Actions on Living Cells, Praeger, New York, 1985. 

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