Helicobacter pylori base-excision restriction enzyme in stomach carcinogenesis

Masaki Fukuyo; Noriko Takahashi; Katsuhiro Hanada; Ken Ishikawa; Česlovas Venclovas; Koji Yahara; Hideo Yonezawa; Takeshi Terabayashi; Yukako Katsura; Naoki Osada; Atsushi Kaneda; M. Constanza Camargo; Charles S Rabkin; Ikuo Uchiyama; Takako Osaki; Ichizo Kobayashi

doi:10.1093/pnasnexus/pgaf244

Title	Helicobacter pylori base-excision restriction enzyme in stomach carcinogenesis
Authors	Fukuyo, Masaki ; Takahashi, Noriko ; Hanada, Katsuhiro ; Ishikawa, Ken ; Venclovas, Česlovas ; Yahara, Koji ; Yonezawa, Hideo ; Terabayashi, Takeshi ; Katsura, Yukako ; Osada, Naoki ; Kaneda, Atsushi ; Camargo, M. Constanza ; Rabkin, Charles S ; Uchiyama, Ikuo ; Osaki, Takako ; Kobayashi, Ichizo
DOI	10.1093/pnasnexus/pgaf244
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Is Part of	PNAS Nexus.. Oxford : Oxford University Press. 2025, vol. 4, iss. 8, p. [1-12].. eISSN 2752-6542
Keywords [eng]	bacterial oncogenesis ; gastric cancer ; genotoxin ; PabI ; restriction glycosylase
Abstract [eng]	Many recent lines of evidence from the human microbiome and other fields indicate bacterial involvement in various types of cancer. Helicobacter pylori has been recognized as the major cause of stomach cancer (gastric cancer), but the mechanism by which it destabilizes the human genome to cause cancer remains unclear. Our recent studies have identified a unique family of toxic restriction enzymes that excise a base (A: adenine) from their recognition sequence (5′-GTAC). At the resulting abasic sites (5′-GT-C), its inherent endonuclease activity or that of a separate endonuclease may yield atypical strand breaks that resist repair by ligation. Here, we present evidence demonstrating involvement of its H. pylori member, HpPabI, in stomach carcinogenesis: (i) Association of intact HpPabI gene with gastric cancer in the global H. pylori Genome Project and the open genomes; (ii) Frequent mutations at A in 5′-GTAC in the gastric cancer genomes as well as in H. pylori genomes; (iii) Its induction of chromosomal double-strand breaks in infected human cells and of mutagenesis in bacterial test systems. In addition, its unique regions that interact with DNA exhibit signs of diversifying selection. Our further analysis revealed similar oncogenic bacterium-restriction-enzyme pairs for other types of cancer. These results set another stage for cancer research and medicine around oncogenic restriction enzymes.
Published	Oxford : Oxford University Press
Type	Journal article
Language	English
Publication date	2025
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„Helicobacter pylori base-excision restriction enzyme in stomach carcinogenesis“