Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis

Satoshi Imai, Takuya Ooki, Naoko Murata-Kamiya, Daisuke Komura, Kamrunnesa Tahmina, Weida Wu, Atsushi Takahashi-Kanemitsu, Christopher Takaya Knight, Akiko Kunita, Nobumi Suzuki, Adriana A. Del Valle, Mayo Tsuboi, Masahiro Hata, Yoku Hayakawa, Naomi Ohnishi, Koji Ueda, Masashi Fukayama, Tetsuo Ushiku, Shumpei Ishikawa, Masanori Hatakeyama

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. It hereby induces BRCAness that promotes DNA double-strand breaks (DSBs) while disabling error-free homologous recombination-mediated DNA repair. The CagA/PAR1b interaction also stimulates Hippo signaling that circumvents apoptosis of DNA-damaged cells, giving cells time to repair DSBs through error-prone mechanisms. The DSB-activated p53-p21Cip1 axis inhibits proliferation of CagA-delivered cells, but the inhibition can be overcome by p53 inactivation. Indeed, sequential pulses of CagA in TP53-mutant cells drove somatic mutation with BRCAness-associated genetic signatures. Expansion of CagA-delivered cells with BRCAness-mediated genome instability, from which CagA-independent cancer-predisposing cells arise, provides a plausible “hit-and-run mechanism” of H. pylori CagA for gastric carcinogenesis.

Original languageEnglish
Pages (from-to)941-958.e10
JournalCell Host and Microbe
Volume29
Issue number6
DOIs
Publication statusPublished or Issued - 9 Jun 2021

Keywords

  • BRCA1
  • BRCAness
  • CagA
  • DNA double-strand break
  • Helicobacter pylori
  • PAR1b
  • gastric cancer
  • genome instability
  • homologous recombination
  • replication fork instability

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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