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Identification and functional characterization of the promoter region of the human MSH6 gene


Szadkowski, M; Jiricny, J (2002). Identification and functional characterization of the promoter region of the human MSH6 gene. Genes, Chromosomes & Cancer, 33(1):36-46.

Abstract

Postreplicative mismatch repair (MMR) corrects polymerase errors arising during DNA replication. Consistent with this role, the Saccharomyces cerevisiae MMR genes MSH2, MSH6, and PMS1 were reported to be transcriptionally upregulated during late G(1) phase of the cell cycle. Surprisingly, despite the high degree of conservation of the MMR system in evolution, the human MMR genes studied to date, MSH2, MLH1, and PMS2, appear to be transcribed from classical housekeeping promoters, and the amounts of the polypeptides encoded by them fluctuate little during the cell cycle. Only the amounts of the 160-kDa MSH6 protein were reported to vary, both during development and following stimulation of cell growth. Moreover, transcription of this gene was found to be downregulated by CpG methylation of the promoter region in a subset of clones treated with alkylating agents. In an attempt to understand the molecular basis underlying these phenomena, we isolated the 5' region of the MSH6 gene and subjected it to functional analysis. We now show that the MSH6 gene is also transcribed from a classical housekeeping gene promoter. Despite housing putative binding sites for the transcription factors AP1, NF-kappaB, and MTF-1, the MSH6 promoter failed to respond to ionizing radiation or heavy metals. Interestingly, MSH6 transcription was upregulated during late G(1) phase, even though the levels of the protein remained essentially constant during the cell cycle.

Postreplicative mismatch repair (MMR) corrects polymerase errors arising during DNA replication. Consistent with this role, the Saccharomyces cerevisiae MMR genes MSH2, MSH6, and PMS1 were reported to be transcriptionally upregulated during late G(1) phase of the cell cycle. Surprisingly, despite the high degree of conservation of the MMR system in evolution, the human MMR genes studied to date, MSH2, MLH1, and PMS2, appear to be transcribed from classical housekeeping promoters, and the amounts of the polypeptides encoded by them fluctuate little during the cell cycle. Only the amounts of the 160-kDa MSH6 protein were reported to vary, both during development and following stimulation of cell growth. Moreover, transcription of this gene was found to be downregulated by CpG methylation of the promoter region in a subset of clones treated with alkylating agents. In an attempt to understand the molecular basis underlying these phenomena, we isolated the 5' region of the MSH6 gene and subjected it to functional analysis. We now show that the MSH6 gene is also transcribed from a classical housekeeping gene promoter. Despite housing putative binding sites for the transcription factors AP1, NF-kappaB, and MTF-1, the MSH6 promoter failed to respond to ionizing radiation or heavy metals. Interestingly, MSH6 transcription was upregulated during late G(1) phase, even though the levels of the protein remained essentially constant during the cell cycle.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2002
Deposited On:09 Jul 2010 09:10
Last Modified:05 Apr 2016 13:57
Publisher:Wiley-Blackwell
ISSN:1045-2257
Publisher DOI:10.1002/gcc.1211
PubMed ID:11746986
Permanent URL: http://doi.org/10.5167/uzh-31259

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