Dataset Information

Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide.

ABSTRACT: Members of hereditary nonpolyposis colon cancer (HNPCC) families harboring heterozygous germline mutations in the DNA mismatch repair genes hMSH2 or hMLH1 present with tumors generally two to three decades earlier than individuals with nonfamilial sporadic colon cancer. We searched for phenotypic features that might predispose heterozygous cells from HNPCC kindreds to malignant transformation. hMSH2(+/-) lymphoblastoid cell lines were found to be on average about 4-fold more tolerant than wild-type cells to killing by the methylating agent temozolomide, a phenotype that is invariably linked with impairment of the mismatch repair system. This finding was associated with an average 2-fold decrease of the steady-state level of hMSH2 protein in hMSH2(+/-) cell lines. In contrast, hMLH1(+/-) heterozygous cells were indistinguishable from normal controls in these assays. Thus, despite the fact that HNPCC families harboring mutations in hMSH2 or hMLH1 cannot be distinguished clinically, the early stages of the carcinogenic process in hMSH2 and hMLH1 mutation carriers may be different. Should hMSH2(+/-) colonocytes and lymphoblasts harbor a similar phenotype, the increased tolerance of the former to DNA-damaging agents present in the human colon may play a key role in the initiation of the carcinogenic process.

SUBMITTER: Marra G

PROVIDER: S-EPMC34640 | biostudies-literature | 2001 Jun

REPOSITORIES: biostudies-literature

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Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide.

Marra G G D'Atri S S Corti C C Bonmassar L L Cattaruzza M S MS Schweizer P P Heinimann K K Bartosova Z Z Nyström-Lahti M M Jiricny J J

Proceedings of the National Academy of Sciences of the United States of America 20010601 13

Members of hereditary nonpolyposis colon cancer (HNPCC) families harboring heterozygous germline mutations in the DNA mismatch repair genes hMSH2 or hMLH1 present with tumors generally two to three decades earlier than individuals with nonfamilial sporadic colon cancer. We searched for phenotypic features that might predispose heterozygous cells from HNPCC kindreds to malignant transformation. hMSH2(+/-) lymphoblastoid cell lines were found to be on average about 4-fold more tolerant than wild-t ...[more]

PMID: 11416201

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Project description:Gene expression varies widely between individuals of a population, and regulatory change can underlie phenotypes of evolutionary and biomedical relevance. A key question in the field is how DNA sequence variants impact gene expression, with most mechanistic studies to date focused on the effects of genetic change on regulatory regions upstream of protein-coding sequence. By contrast, the role of RNA 3'-end processing in regulatory variation remains largely unknown, owing in part to the challenge of identifying functional elements in 3' untranslated regions. In this work, we conducted a genomic survey of transcript ends in lymphoblastoid cells from genetically distinct human individuals. Our analysis mapped the cis-regulatory architecture of 3' gene ends, finding that transcript end positions did not fall randomly in untranslated regions, but rather preferentially flanked the locations of 3' regulatory elements, including miRNA sites. The usage of these transcript length forms and motifs varied across human individuals, and polymorphisms in polyadenylation signals and other 3' motifs were significant predictors of expression levels of the genes in which they lay. Independent single-gene experiments confirmed the effects of polyadenylation variants on steady-state expression of their respective genes, and validated the regulatory function of 3' cis-regulatory sequence elements that mediated expression of these distinct RNA length forms. Focusing on the immune regulator IRF5, we established the effect of natural variation in RNA 3'-end processing on regulatory response to antigen stimulation. Our results underscore the importance of two mechanisms at play in the genetics of 3'-end variation: the usage of distinct 3'-end processing signals and the effects of 3' sequence elements that determine transcript fate. Our findings suggest that the strategy of integrating observed 3'-end positions with inferred 3' regulatory motifs will prove to be a critical tool in continued efforts to interpret human genome variation.

Dataset Information

Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide.

Publications

Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide.

Similar Datasets

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