Important Role in Camptothecin Resistance X-ray Repair Cross-Complementing Gene I Protein Plays an
نویسندگان
چکیده
X-ray repair cross-complementing gene I protein (XRCC1) in complex with DNA polymerase , DNA ligase III, and poly(ADP-ribose) polymerase is important in the base excision repair process. Previously, we isolated camptothecin (CPT)-resistant cell lines (KB100 and KB300) from the human epidermoid carcinoma cell line KB by exposure to CPT. From these CPT-resistant cell lines, their revertants (KB100 and KB300), which lost most of their CPT-resistant phenotype during passage in the absence of CPT, were established. In this study, we found the expression levels of XRCC1 protein in KB100 and KB300 were >5-fold more than in their respective revertant cell lines, whereas there was no difference in the expression of XRCC1-associated proteins such as DNA polymerase , DNA ligase III, poly(ADP-ribose) polymerase, and apurinic/apyrimidinic endonuclease. The degree of CPT resistance was relatively correlated with the XRCC1 protein amount. We also found XRCC1 gene amplification in CPT-resistant KB100 and KB300 cell lines. To confirm a correlation between overexpression of XRCC1 and CPT resistance, we transfected the XRCC1 gene into KB100 and obtained two different transfected cell lines (clones 14 and 16). The expression levels of XRCC1 in the transfected cell lines were higher than in KB100 but lower than in KB100 with no difference in XRCC1-associated protein expression levels. Resistance to CPT in transfected cell lines was 2–2.5-fold higher than in KB100 in regard to growth inhibition and 4-fold higher with respect to clonogenicity. Transfected cell lines also showed increased resistance to other topoisomerase I poisons. However, the cytotoxicity of VP-16 and cisplatin was similar in both the transfected cells and KB100. Similar to our CPTresistant cell lines, the resistance of transfected cell lines was reversed by treatment with 3-aminobenzamide. These results indicate that CPT resistance in our cells could be partly attributable to the overexpression of XRCC1.
منابع مشابه
X-ray repair cross-complementing gene I protein plays an important role in camptothecin resistance.
X-ray repair cross-complementing gene I protein (XRCC1) in complex with DNA polymerase beta, DNA ligase III, and poly(ADP-ribose) polymerase is important in the base excision repair process. Previously, we isolated camptothecin (CPT)-resistant cell lines (KB100 and KB300) from the human epidermoid carcinoma cell line KB by exposure to CPT. From these CPT-resistant cell lines, their revertants (...
متن کاملAssociation of Arg194Trp, Arg280His and Arg399Gln Polymorphisms in X-Ray Repair Cross-Complementing Group 1 Gene and Risk of Differentiated Thyroid Carcinoma in Iran
Background: X-ray repair cross-complementing group 1 (XRCC1) gene is a DNA repair gene and its non-synonymous single nucleotide polymorphisms (SNP) may influence DNA repair capacity which has been considered as a modifying risk factor for cancer development. Methods: A case-control study was conducted to investigate impact of three frequently studied polymorphisms (Arg194Trp, Arg280His and Arg3...
متن کاملAssociation between Polymorphisms of X-ray Repair Cross Complementing 5 and 6 Promoter Genes and the Risk of Metastatic Breast Cancer
Background and Objective: Breast cancer is the second leading cause of cancer-related death in women. Better individualized treatment needs novel prognostic predictors. X-ray repair cross complementing XRCC5 and XRCC6 are coding genes of the Ku protein complex (key components of the non-homologous end-joining [NHEJ] pathway), which could serve as prognostic factors in breast cancer. Hence, in t...
متن کاملAssociation of -77T>C and Arg194trp polymorphisms of XRCC1 with risk of coronary artery diseases in Iranian population
Objective(s): Coronary artery disease (CAD) is the leading cause of death in both male and female worldwide. The main cause of CAD is the atherosclerosis of coronary arteries, which is, mostly caused by genetic alteration. 50% of such cases occur in mitotic cells where single-strand breaks occur spontaneously or due to ionizing radiation. X-ray repair cross-complementing protein 1 (XRCC1) as a ...
متن کاملPARP1–TDP1 coupling for the repair of topoisomerase I–induced DNA damage
Poly(ADP-ribose) polymerases (PARP) attach poly(ADP-ribose) (PAR) chains to various proteins including themselves and chromatin. Topoisomerase I (Top1) regulates DNA supercoiling and is the target of camptothecin and indenoisoquinoline anticancer drugs, as it forms Top1 cleavage complexes (Top1cc) that are trapped by the drugs. Endogenous and carcinogenic DNA lesions can also trap Top1cc. Tyros...
متن کامل