Inhibition of polarity-regulating kinase PAR1b contributes to Helicobacter pylori inflicted DNA Double Strand Breaks in gastric cells

Andrea Zamperone, David Cohen, Markus Stein, Charlotte Viard, Anne Muesch

Research output: Contribution to journalArticle

Abstract

The serine/threonine kinase Par1 is a core component of the machinery that sets up polarity in the embryo and regulates cell fate decisions but its role in the homeostasis of adult tissues is poorly understood. Inhibition of Par1 by the bacterium Helicobacter pylori (H. pylori) represents the only established pathology that affects Par1 function in an adult epithelium. Thus, during chronic H. pylori infection of the gastric mucosa Par1 is one of the targets of the non-obligate H.pylori cytotoxic protein and oncogene CagA, which stimulates inflammation and triggers morphological changes, both believed to contribute to the gastric cancer risk imposed by H. pylori infection. Based on Par1’s role in cell polarity, it has been speculated that Par1 inhibition affects epithelial polarity. Here we report the unexpected finding that CagA-mediated Par1-inhibition promotes the generation of DNA Double Strand Breaks in primary gastric epithelial cells, which likely contributes to the reported accumulation of mutations in chronically infected mucosal cells. Abbreviations: AGS: human gastric adenocarcinoma cell line; CM: CagA Multimerization (and Par1 binding) domain; H. pylori: Helicobacter pylori; DSB: Double Strand Break; HGECs: human (primary) gastric epithelial cells; IB: immunoblot; IF: immunofluorescence; MOI: Multiplicity of Infection; ROS: reactive oxygen species; Par1: Partitioning Defective 1 kinase; WT: wild type.

Original languageEnglish (US)
JournalCell Cycle
DOIs
StateAccepted/In press - Jan 1 2019

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Double-Stranded DNA Breaks
Helicobacter pylori
Stomach
Phosphotransferases
Helicobacter Infections
Epithelial Cells
Cell Polarity
Protein-Serine-Threonine Kinases
Oncogene Proteins
Pylorus
Gastric Mucosa
Stomach Neoplasms
Fluorescent Antibody Technique
Reactive Oxygen Species
Adenocarcinoma
Homeostasis
Embryonic Structures
Epithelium
Pathology
Inflammation

Keywords

  • DNA Double Strand Breaks
  • gastric epithelial cells
  • Helicobacter pylori
  • MARK2
  • Par1

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Inhibition of polarity-regulating kinase PAR1b contributes to Helicobacter pylori inflicted DNA Double Strand Breaks in gastric cells. / Zamperone, Andrea; Cohen, David; Stein, Markus; Viard, Charlotte; Muesch, Anne.

In: Cell Cycle, 01.01.2019.

Research output: Contribution to journalArticle

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