Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nucleotide excision repair (NER) is the principal pathway for the removal of a wide range of DNA helix-distorting lesions. Two NER subpathways have been identified, i.e. global genome repair (GGR) and transcription-coupled repair (TCR). Little is known about the expression of NER pathways in differentiated cells. We assessed the repair of UV-induced cyclobutane pyrimidine dimers (CPD) and 6-4-photoproducts (6-4 PP) in terminally differentiated myocytes and proliferating fibroblasts isolated from the hearts of neonatal rats. Myocytes and fibroblasts were found to carry out efficient removal of 6-4 PP but display poor repair of CPD by GGR. Furthermore, both cell types were found to carry out TCR of CPD, thus mimicking the repair phenotype of established rodent cell lines. The inefficient repair of CPD at the genome overall level occurs in the absence of massive apoptosis, but goes along with an undetectable level of transcription of the p48 gene, known to be mutated in xeroderma pigmentosum group E (XP-E) patients and recently proposed to be essential for repair of CPD in nonexpressed DNA. Taken together, the results suggest that primary non-dividing cardiac myocytes and proliferating fibroblasts from rat heart selectively remove CPD from the transcribed strand of transcriptionally active genes. GGR of CPD is poor due to the absence of p48 expression.
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PMID:Deficient global genome repair of UV-induced cyclobutane pyrimidine dimers in terminally differentiated myocytes and proliferating fibroblasts from the rat heart. 1464 60

Inhibition of DNA repair processes has been suggested as one predominant mechanism in arsenic co-genotoxicity. However, the underlying mode of action responsible for DNA repair inhibition by arsenic remains elusive. To further elucidate the mechanism of repair inhibition by arsenic, we examined the effect of trivalent inorganic and methylated arsenic metabolites on the repair of benzo(a)pyrene diol epoxide (BPDE)-DNA adducts in normal human primary fibroblasts and their effect on repair-related protein expression. We observed that monomethylarsonous acid (MMA(III)) was the most potent inhibitor of the DNA repair. MMA(III) did not change the expression levels of some key repair proteins involved upstream of the dual incision in the global nucleotide excision repair (NER) pathway, including p48, XPC, xeroderma pigmentosum complementation group A (XPA), and p62-TFIIH. However, it led to a marked impairment of p53 induction in response to BPDE treatment. The abrogated p53 expression translated into reduced p53 DNA-binding activity, suggesting a possibility of downregulating downstream repair genes by p53. A p53-null cell line failed to exhibit the inhibitory effect of MMA(III) on NER, implicating a role for p53 in the NER inhibition by MMA(III). Further investigation revealed that MMA(III) dramatically inhibited p53 phosphorylation at serine 15, implying that MMA(III) destabilized p53 by inhibiting its phosphorylation. Because p53 is required for proficient global NER, our data suggest that arsenic inhibits NER through suppressing p53 induction in response to DNA damage in cells with normal p53 gene expression.
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PMID:Attenuation of DNA damage-induced p53 expression by arsenic: a possible mechanism for arsenic co-carcinogenesis. 1808 31


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