Understanding the role of the Q338H MUTYH variant in oxidative damage repair

Eleonora Turco, Ilenia Ventura, Anna Minoprio, Maria Teresa Russo, Paola Torreri, Paolo Degan, Sara Molatore, Guglielmina Nadia Ranzani, Margherita Bignami, Filomena Mazzei

Research output: Contribution to journalArticlepeer-review


The MUTYH DNA-glycosylase is indirectly engaged in the repair of the miscoding 7,8-dihydro-8-oxo-20-deoxyguanine (8-oxodG) lesion by removing adenine erroneously incorporated opposite the oxidized purine. Inherited biallelic mutations in the MUTYH gene are responsible for a recessive syndrome, the MUTYH-associated polyposis (MAP), which confers an increased risk of colorectal cancer. In this study, we functionally characterized the Q338H variant using recombinant proteins, as well as cell-based assays. This is a common variant among human colorectal cancer genes, which is generally considered, unrelated to the MAP phenotype but recently indicated as a low-penetrance allele. We demonstrate that the Q338H variant retains a wild-type DNA-glycosylase activity in vitro, but it shows a reduced ability to interact with the replication sensor RAD9:RAD1: HUS1 (9-1-1) complex. In comparison with Mutyh-/- mouse embryo fibroblasts expressing a wild-type MUTYH cDNA, the expression of Q338H variant was associated with increased levels of DNA 8-oxodG, hypersensitivity to oxidant and accumulation of the population in the S phase of the cell cycle. Thus, an inefficient interaction of MUTYH with the 9-1-1 complex leads to a repairdefective phenotype, indicating that a proper communication between MUTYH enzymatic function and the S phase checkpoint is needed for effective repair of oxidative damage.

Original languageEnglish
Pages (from-to)4093-4103
Number of pages11
JournalNucleic Acids Research
Issue number7
Publication statusPublished - Apr 2013

ASJC Scopus subject areas

  • Genetics


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