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. 2021 Jun 9;29(6):941-958.e10.
doi: 10.1016/j.chom.2021.04.006. Epub 2021 May 13.

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

Satoshi Imai  1 , Takuya Ooki  1 , Naoko Murata-Kamiya  2 , Daisuke Komura  3 , Kamrunnesa Tahmina  1 , Weida Wu  1 , Atsushi Takahashi-Kanemitsu  1 , Christopher Takaya Knight  1 , Akiko Kunita  4 , Nobumi Suzuki  5 , Adriana A Del Valle  1 , Mayo Tsuboi  5 , Masahiro Hata  5 , Yoku Hayakawa  5 , Naomi Ohnishi  6 , Koji Ueda  6 , Masashi Fukayama  4 , Tetsuo Ushiku  4 , Shumpei Ishikawa  3 , Masanori Hatakeyama  7
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Free article

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

Satoshi Imai et al. Cell Host Microbe. .
Free article

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.

Keywords: BRCA1; BRCAness; CagA; DNA double-strand break; Helicobacter pylori; PAR1b; gastric cancer; genome instability; homologous recombination; replication fork instability.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Comment in

  • Helicobacter pylori: a stealth assassin.
    Wroblewski LE, Peek RM Jr. Wroblewski LE, et al. Trends Cancer. 2021 Sep;7(9):807-808. doi: 10.1016/j.trecan.2021.05.007. Epub 2021 Jun 9. Trends Cancer. 2021. PMID: 34119456 Free PMC article.

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