Deficient Nucleotide Excision Repair in Squamous Cell Carcinoma Cells.

Squamous cell carcinomas (SCCs) are associated with ultraviolet radiation and multiple genetic changes, but the mechanisms leading to genetic instability are unclear. SCC cell lines were compared to normal keratinocytes for sensitivity to ultraviolet radiation, DNA repair kinetics and DNA repair protein expression. Relative to normal keratinocytes, four SCC cell lines were all variably sensitive to ultraviolet radiation and, except for the SCC25 cell line, were deficient in global repair of cyclobutane pyrimidine dimers, although not 6-4 photoproducts.

Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen.

The pathways by which Merkel cell polyomavirus (MCV) infection contributes to the formation of Merkel cell carcinomas are important for understanding the pathogenesis of these cancers. We hypothesized that MCV T antigen suppresses normal responses to ultraviolet radiation (UVR)-induced DNA damage. An MCV-infected cell line (MKL-1) exhibited UVR hypersensitivity, impaired repair of DNA lesions and cell cycle arrest after UVR, as well as reduced levels of the DNA damage recognition protein, XPC.

Functional relevance of the histone gammaH2Ax in the response to DNA damaging agents.

The phosphorylation of H2Ax on its S139 site, γH2Ax, is important during DNA double-strand repair and is considered necessary for assembly of repair complexes, but its functional role after other kinds of DNA damage is less clear. We have measured the survival of isogenic mouse cell lines with the H2Ax gene knocked out, and replaced with wild-type or mutant (S139A) H2Ax genes, exposed to a range of agents with varied mechanisms of DNA damage. Knockout and mutant cells were sensitive to γ-rays, etoposide, temozolamide, and endogenously generated reactive oxygen species, each of which can include double-strand breaks among their spectra of DNA lesions.

Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63.

While many p53-deficient cell types are impaired in global genomic nucleotide excision repair of cyclobutane pyrimidine dimers (CPDs), human epidermal keratinocytes expressing human papillomavirus type 16 E6 and E7 are p53 deficient and yet maintain repair of CPD. We hypothesized that the p53 homolog, p63, may participate in governing global repair instead of p53 in keratinocytes. Following ultraviolet radiation (UVR) of E6/E7 keratinocytes, depletion of p63 but not of p73 impaired global genomic repair of CPD relative to control cells.