UVB Irradiation, Mismatch Repair and Cutaneous Melanoma
Msh2 is one of the genes involved in DNA-mismatch repair. Mutations in the coding region of the human gene (hmsh2) have been shown to be directly involved in microsatellite instability in hereditary nonpolyposis colorectal tumors. Examination of the promoter region of hmsh2 revealed a site with homology to the P53 consensus binding sequence. Using gel mobility shift experiments we were able to show that purified p53 has at least in vitro the potential to specifically bind the hmsh2-p53 motif. The binding activity was even stronger than the binding activity measured with the p53-consensus site. These data identify the hmsh2 gene as a possible novel p53-regulated target gene and indicate a direct involvement of p53 in repair mechanisms via DNA binding of a mismatch repair gene. Following UVB irradiation of human keratinocytes in cell culture we were able to transiently induce P53 expression with a subsequent increase in msh2-promoter binding activity, indicating a role of mismatch repair control after UVB damage. We are currently under way to examine in this context the involvement of microsatellite instability and the correlation of msh2 and p53 mutations in the pathogenesis of cutaneous melanoma using sections from paraffin-embedded tumor-tissue.
KeywordsMismatch Repair Cutaneous Melanoma Mismatch Repair Gene Satellite Instability Hmsh2 Gene
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