Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human breast carcinoma (MCF7-MLNr) cells resistant to the bifunctional drugs L-phenylalanine mustard (L-PAM, 5-fold resistance), mechlorethamine (9-fold), cisplatin (3-fold), and BCNU (3-fold) were used to investigate the role of DNA repair in the development of resistance to alkylating agents. We have previously shown that neither L-PAM transport and metabolism nor glutathione-associated enzymes were altered in MCF7-MLNr cells, compared to the sensitive cells MCF7-WT. This study shows that treatment of pRSV-CAT plasmid with L-PAM at concentrations up to 1 microM proportionally inhibit the expression of chloramphenicol acetyl transferase (CAT) activity, while higher concentrations abolished CAT activity. pRSV-CAT reactivation was significantly increased when plasmid was transfected into MCF7-MLNr cells, compared to MCF7-WT cells. This indicates that resistant cells have more efficient capacity to recognize and repair L-PAM induced DNA damage. The mRNA expression of DNA nucleotide excision repair genes ERCC1, XPD (ERCC2), XPB (ERCC3), and polymerase beta was found to be similar in both the MCF7-WT and MCF7-MLNr cells. Western blot analysis also reveals no difference in the expression of ERCC1, AP endonuclease, poly (ADP-ribose) polymerase, and alkyl-N-purine-DNA glycosylase proteins. The lack of correlation between enhanced host cell reactivation capacity in resistant cells, and the expression of these specific DNA repair genes suggests that proteins encoded by these genes are not rate limiting steps for resistance to bi-functional alkylating drugs in human breast cancer cells.
 ...
PMID:Enhanced host cell reactivation capacity and expression of DNA repair genes in human breast cancer cells resistant to bi-functional alkylating agents. 749 Nov 21

The repair-deficient mutant rodent cell lines UV20 and UV41, which are defective in the ERCC1/ERCC4[XPF]-mediated 5'-endonuclease activity, are unusually sensitive to gamma-irradiation under hypoxic (but not oxic) conditions. Because this 5'-endonuclease appears to be involved in two distinct (but overlapping) DNA-repair pathways-the nucleotide excision repair pathway and the recombination-dependent pathway for the removal of DNA interstrand cross-links-it is unclear which of these defective activities is responsible for the hypoxic radiosensitivity of UV20 and UV41 cells. Accordingly, we have extended these measurements to the UV5 and UV24 lines which carry mutations in the ERCC2[XPD] and ERCC3[XPB] genes, respectively; both of these genes encode DNA helicases. These two mutants display a sensitivity to ultraviolet light that is similar to that of UV20 and UV41 cells, reflecting their defect in the incision step of the nucleotide excision repair pathway. However, neither UV5 nor UV24 cells are especially cross-sensitive to agents that produce DNA interstrand cross-links, suggesting that the ERCC2 and ERCC3 activities are not crucial for the repair of these lesions. We show that neither UV5 nor UV24 cells exhibit the unusual hypoxic radiosensitivity that characterizes UV20 and UV41 cells. Based on these data and on a comparison of the patterns of cross-sensitivity of these various mutants to other DNA-damaging agents, we conclude that the increased hypoxic radiosensitivity observed in the UV20 and UV41 mutants is due to a defect in the ERCC1/ERCC4-dependent pathway for the repair of DNA cross-links and not in the nucleotide excision repair pathway. The evidence suggests that this sensitivity may be mediated by some type of radiation-induced cross-links, possibly DNA-protein cross-links.
 ...
PMID:The importance of the ERCC1/ERCC4[XPF] complex for hypoxic-cell radioresistance does not appear to derive from its participation in the nucleotide excision repair pathway. 896 Jan 33