Reduced host cell reactivation of oxidative DNA damage in human cells deficient in the mismatch repair gene hMSH2.
نویسندگان
چکیده
Germ line mutations in the mismatch repair (MMR) genes hMSH2 and hMLH1 account for approximately 98% of hereditary non-polyposis colorectal cancers. In addition, there is increasing evidence for an involvement of MMR gene expression in the response of cells to UV-induced skin cancer. The link between MMR and skin cancer suggests an involvement of MMR gene expression in the response of skin cells to UV-induced DNA damage. In this report, we have used two reporter gene assays to examine the role of hMSH2 and hMLH1 in the repair of oxidative DNA damage induced by UVA light and DNA damage caused by methylene blue plus visible light (MB+VL). UVA and MB+VL produce 8-hydroxyguanines in DNA that are repaired by base excision repair (BER). AdHCMVlacZ is a replication-deficient recombinant adenovirus that expresses the beta-galactosidase (beta-gal) reporter gene under the control of the human cytomegalovirus (CMV) immediate-early promoter. We show a reduced host cell reactivation for beta-gal expression of UVA-treated and MB+VL-treated AdHCMVlacZ in hMSH2-deficient LoVo human colon adenocarcinoma cells compared to their hMSH2-proficient counterpart SW480 cells, but not in hMLH1-deficient HCT116 human colon adenocarcinoma cells compared to hMLH1-proficient HCT116-chr3 cells. We have also reported previously that enhanced expression of the undamaged AdHCMVlacZ reporter gene is induced by the pre-treatment of cells with lower levels of the DNA-damaging agent and to higher expression levels in transcription-coupled repair (TCR)-deficient compared to TCR-proficient cells. Here we show that pre-treatment of cells with UVA or MB+VL enhanced expression of the undamaged reporter gene to a higher level in LoVo compared to SW480 cells but there was little or no difference in HCT116 compared to HCT116-chr3 cells. These results suggest a substantial involvement of hMSH2 but little or no involvement of hMLH1 in the repair of UVA- and MB+VL-induced oxidative DNA damage by BER.
منابع مشابه
Differential involvement of the human mismatch repair proteins, hMLH1 and hMSH2, in transcription-coupled repair.
Defects in DNA mismatch repair have been associated with both hereditary and sporadic forms of cancer. Recently, it has been shown that human cell lines deficient in mismatch repair were also defective in the transcription-coupled repair (TCR) of UV-induced DNA damage. We examined whether TCR of ionizing radiation-induced DNA damage also requires the genes involved in DNA mismatch repair. Cells...
متن کاملDetection of an involvement of the human mismatch repair genes hMLH1 and hMSH2 in nucleotide excision repair is dependent on UVC fluence to cells.
There is conflicting evidence for the role of the mismatch repair (MMR) genes hMLH1 and hMSH2 in the transcription-coupled repair (TCR) pathway of nucleotide excision repair. In the present work, we have examined the role of these MMR genes in nucleotide excision repair using two reporter gene assays. AdHCMVlacZ is a replication-deficient recombinant adenovirus that expresses the beta-galactosi...
متن کاملMSH2-deficient human cells exhibit a defect in the accurate termination of homology-directed repair of DNA double-strand breaks.
Mutations in the mismatch repair (MMR) genes hMSH2 and hMLH1 have been associated with hereditary nonpolyposis colorectal cancer. Tumor cell lines that are deficient in MMR exhibit a high mutation rate, a defect in the response to certain types of DNA damage and in transcription-coupled repair, as well as an increase in the rate of gene amplification. We show here that hMSH2-deficient tumor cel...
متن کاملDNA mismatch repair enzyme expression in synovial tissue.
BACKGROUND Oxidative stress in RA synovial tissue can cause DNA damage and suppress the DNA mismatch repair (MMR) system in cultured synoviocytes. This mechanism includes two enzyme complexes, hMutSalpha (hMSH2/hMSH6) and hMutSbeta (hMSH2/hMSH3). OBJECTIVE To examine the expression and distribution of MMR enzymes in synovial tissues from patients with arthritis and from normal subjects. MET...
متن کاملApoptosis induced by overexpression of hMSH2 or hMLH1.
Mutations of the mismatch repair genes hMSH2 and hMLH1 have been found in a high proportion of individuals with hereditary nonpolyposis colon cancer (HNPCC), establishing the link between mismatch repair and cancer. Tumor cell lines that are deficient in mismatch repair develop a mutator phenotype that appears to drive the accumulation of mutations required for tumor development. However, mutat...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Mutagenesis
دوره 22 3 شماره
صفحات -
تاریخ انتشار 2007