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 journalArticle

24 Citations (Scopus)

Abstract

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
Volume41
Issue number7
DOIs
Publication statusPublished - Apr 2013

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DNA Glycosylases
Colorectal Neoplasms
S Phase Cell Cycle Checkpoints
Phenotype
Aptitude
Penetrance
Neoplasm Genes
Adenine
S Phase
Recombinant Proteins
Oxidants
Cell Cycle
Hypersensitivity
Embryonic Structures
Complementary DNA
Fibroblasts
Alleles
Communication
Mutation
DNA

ASJC Scopus subject areas

  • Genetics

Cite this

Turco, E., Ventura, I., Minoprio, A., Russo, M. T., Torreri, P., Degan, P., ... Mazzei, F. (2013). Understanding the role of the Q338H MUTYH variant in oxidative damage repair. Nucleic Acids Research, 41(7), 4093-4103. https://doi.org/10.1093/nar/gkt130

Understanding the role of the Q338H MUTYH variant in oxidative damage repair. / Turco, Eleonora; Ventura, Ilenia; Minoprio, Anna; Russo, Maria Teresa; Torreri, Paola; Degan, Paolo; Molatore, Sara; Ranzani, Guglielmina Nadia; Bignami, Margherita; Mazzei, Filomena.

In: Nucleic Acids Research, Vol. 41, No. 7, 04.2013, p. 4093-4103.

Research output: Contribution to journalArticle

Turco, E, Ventura, I, Minoprio, A, Russo, MT, Torreri, P, Degan, P, Molatore, S, Ranzani, GN, Bignami, M & Mazzei, F 2013, 'Understanding the role of the Q338H MUTYH variant in oxidative damage repair', Nucleic Acids Research, vol. 41, no. 7, pp. 4093-4103. https://doi.org/10.1093/nar/gkt130
Turco, Eleonora ; Ventura, Ilenia ; Minoprio, Anna ; Russo, Maria Teresa ; Torreri, Paola ; Degan, Paolo ; Molatore, Sara ; Ranzani, Guglielmina Nadia ; Bignami, Margherita ; Mazzei, Filomena. / Understanding the role of the Q338H MUTYH variant in oxidative damage repair. In: Nucleic Acids Research. 2013 ; Vol. 41, No. 7. pp. 4093-4103.
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