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
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Department of Infectious Diseases, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan.
PNAS Nexus. 2025 Aug 5;4(8):pgaf244. doi: 10.1093/pnasnexus/pgaf244. eCollection 2025 Aug.
Many recent lines of evidence from the human microbiome and other fields indicate bacterial involvement in various types of cancer. 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 (: adenine) from their recognition sequence (5'-GTC). At the resulting abasic sites (5'-GTC), 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 member, PabI, in stomach carcinogenesis: (i) Association of intact PabI gene with gastric cancer in the global Genome Project and the open genomes; (ii) Frequent mutations at in 5'-GTC in the gastric cancer genomes as well as in 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.
来自人类微生物组和其他领域的许多最新证据表明，细菌与多种类型的癌症有关。幽门螺杆菌已被公认为是胃癌的主要病因，但其破坏人类基因组导致癌症的机制仍不清楚。我们最近的研究发现了一个独特的毒性限制酶家族，它们从识别序列（5'-GTC）中切除一个碱基（腺嘌呤）。在产生的无碱基位点（5'-GTC），其固有的内切酶活性或另一种内切酶的活性可能会产生非典型的链断裂，这种链断裂无法通过连接进行修复。在这里，我们提供证据证明其成员PabI参与胃癌发生：（i）在全球人类基因组计划和开放基因组中，完整的PabI基因与胃癌有关；（ii）在胃癌基因组以及幽门螺杆菌基因组中，5'-GTC中的腺嘌呤频繁发生突变；（iii）它在受感染的人类细胞中诱导染色体双链断裂，并在细菌测试系统中诱导诱变。此外，其与DNA相互作用的独特区域表现出多样化选择的迹象。我们的进一步分析揭示了其他类型癌症中类似的致癌细菌-限制酶对。这些结果为围绕致癌限制酶的癌症研究和医学奠定了新的基础。
