Oncotarget

Research Papers:

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 and Eugenia Dogliotti

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Oncotarget. 2017; 8:84827-84840. https://doi.org/10.18632/oncotarget.10185

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Abstract

Valeria Simonelli1,*, Giuseppe Leuzzi1,*, Giorgia Basile1,*, Mariarosaria D’Errico1, Paola Fortini1, Annapaola Franchitto1, Valentina Viti2, Ashley R. Brown3, Eleonora Parlanti1, Barbara Pascucci4, Domenico Palli5, Alessandro Giuliani1, Fabio Palombo6, Robert W. Sobol3,7,8, Eugenia Dogliotti1

1Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy

2Istituto di Ricerche Biologia Molecolare P. Angeletti (IRBM), Pomezia (Rome), Italy

3University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA

4Institute of Cristallography, Consiglio Nazionale delle Ricerche, Monterotondo Stazione, Rome, Italy

5Molecular and Nutritional Epidemiology Unit, CSPO, Scientific Institute of Tuscany, Florence, Italy

6Takis Biotech, Castel Romano, Rome, Italy

7Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

8Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA

*These authors have contributed equally to this work

Correspondence to:

Valeria Simonelli, email: [email protected]

Eugenia Dogliotti, email: [email protected]

Keywords: DNA repair, alkylation damage, gastric cancer, DNA polymerase β, mismatch repair

Received: September 02, 2015     Accepted: May 23, 2016     Published: June 20, 2016

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.


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