base-excision restriction enzyme in stomach carcinogenesis.

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.