Journal Article

Cells with pathogenic biallelic mutations in the human <i>MUTYH</i> gene are defective in DNA damage binding and repair

Antony R. Parker, Oliver M. Sieber, Chanjuan Shi, Li Hua, Masashi Takao, Ian P. Tomlinson and James R. Eshleman

in Carcinogenesis

Volume 26, issue 11, pages 2010-2018
Published in print November 2005 | ISSN: 0143-3334
Published online June 2005 | e-ISSN: 1460-2180 | DOI:
Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair

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Inherited biallelic mutations in the human MUTYH gene are responsible for the recessive syndrome—adenomatous colorectal polyposis (MUTYH associated polyposis, MAP)—which significantly increases the risk of colorectal cancer (CRC). Defective MUTYH activity causes G:C to T:A transversions in tumour APC and other genes thereby altering genomic integrity. We report that of the four established cell lines, derived from patients with the MAP phenotype and containing biallelic MUTYH mutations, three contain altered expressions of MUTYH protein (MUTYH Y165C−/−, MUTYH 1103delC/G382D and MUTYH Y165C/G382D but not MUTYH G382D−/−), but that all four cell lines have wild type levels of MUTYH mRNA. Mutant MUTYH proteins in these four cell lines possess significantly lowered binding and cleavage activities with heteroduplex oligonucleotides containingA·8-oxoG and 8-oxoA·G mispairs. Transfection of mitochondrial or nuclear MUTYH cDNAs partially correct altered MUTYH expression and activity in these defective cell lines. Finally, we surprisingly find that defective MUTYH may not alter cell survival after hydrogen peroxide and menadione treatments. The Y165C and 1103delC mutations significantly reduce MUTYH protein stability and thus repair activity, whereas the G382D mutation produces dysfunctional protein only suggesting different functional molecular mechanisms by which the MAP phenotype may contribute to the development of CRC.

Keywords: 8-oxoG, 8-hydroxyguanosine; APC; adenomatous polyposis coli; CRC, colorectal cancer; MAP, MUTYH associated polyposis; MMR, mismatch repair; MUTYH, MutY homolog

Journal Article.  6345 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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