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

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