Crosstalk Between Mismatch Repair and Base Excision Repair in Human Gastric Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Nov 22

PMID 29156686

Citations 10

Authors

Valeria Simonelli

Giuseppe Leuzzi

Giorgia Basile

Mariarosaria DErrico

Paola Fortini

Annapaola Franchitto

Valentina Viti

Ashley R Brown

Eleonora Parlanti

Barbara Pascucci

Domenico Palli

Alessandro Giuliani

Fabio Palombo

Robert W Sobol

Eugenia Dogliotti

Affiliations

Soon will be listed here.

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 O-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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