Carcinogenesis Advance Access published online on June 29, 2005
Carcinogenesis, doi:10.1093/carcin/bgi166
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1 Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA; Present address: The Binding Site, ELISA Department, PO Box 11712, Birmingham, B14 4ZB, UK
* To whom correspondence should be addressed. 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. Defective MUTYH activity causes G:C to T:A transversions in tumor APC and other genes thereby altering genomic integrity. We report that of four established cell lines, derived from patients with the MAP phenotype and containing biallelic MUTYH mutations, three contain altered expression of MUTYH protein (MUTYH Y165C -/-, MUTYH 1103delC/G382D, MUTYH Y165C/G382D but not MUTYH G382D -/-, but that all four cell lines have wildtype levels of MUTYH mRNA. Mutant MUTYH proteins in these four cell lines possess significantly lowered binding and cleavage activities with heteroduplex oligonucleotides containing A•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 colorectal cancer
Received February 24, 2005
Revised June 16, 2005
Accepted June 18, 2005
CARCINOGENESIS
Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair
2 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK
3 Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
4 Department of Molecular Genetics, Tohoko University, Sendai, Japan
5 Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA
Antony R. Parker, E-mail: parkerco21229{at}yahoo.com
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