Crosstalk between mismatch repair and base excision repair in human gastric cancer

Valeria Simonelli, Giuseppe Leuzzi, Giorgia Basile, Mariarosaria D'Errico, Paola Fortini, Annapaola Franchitto, Valentina Viti, Ashley R. Brown, Eleonora Parlanti, Barbara Pascucci, Domenico Palli, Alessandro Giuliani, Fabio Palombo, Robert W. Sobol, Eugenia Dogliotti

Research output: Contribution to journalArticle

Abstract

DNA repair gene expression in a set of gastric cancers suggested an inverse association between the expression of the mismatch repair (MMR) gene MLH1 and that of the base excision repair (BER) gene DNA polymerase β (Polβ). To gain insight into possible crosstalk of these two repair pathways in cancer, we analysed human gastric adenocarcinoma AGS cells over-expressing Polβ or Polβ active site mutants, alone or in combination with MLH1 silencing. Next, we investigated the cellular response to the alkylating agent methyl methanesulfonate (MMS) and the purine analogue 6-thioguanine (6-TG), agents that induce lesions that are substrates for BER and/or MMR. AGS cells over-expressing Polβ were resistant to 6-TG to a similar extent as when MLH1 was inactivated while inhibition of O6-methylguanine-DNA methyltransferase (MGMT) was required to detect resistance to MMS. Upon either treatment, the association with MLH1 down-regulation further amplified the resistant phenotype. Moreover, AGS cells mutated in Polβ were hypersensitive to both 6-TG and MMS killing and their sensitivity was partially rescued by MLH1 silencing. We provide evidence that the critical lethal lesions in this new pathway are double strand breaks that are exacerbated when Polβ is defective and relieved when MLH1 is silenced. In conclusion, we provide evidence of crosstalk between MLH1 and Polβ that modulates the response to alkylation damage. These studies suggest that the Polβ/MLH1 status should be taken into consideration when designing chemotherapeutic approaches for gastric cancer.

Original languageEnglish
Pages (from-to)84827-84840
Number of pages14
JournalOncotarget
Volume8
Issue number49
DOIs
Publication statusPublished - Oct 17 2017

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Keywords

  • Alkylation damage
  • DNA polymerase β
  • DNA repair
  • Gastric cancer
  • Mismatch repair

ASJC Scopus subject areas

  • Oncology

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