Inhibition of autophagy aggravates DNA damage response and gastric tumorigenesis via Rad51 ubiquitination in response to <i>H. pylori</i> infection

Abstract

Helicobacter pylori (<i>H. pylori</i>) infection is the strongest known risk factor for the development of gastric cancer. DNA damage response (DDR) and autophagy play key roles in tumorigenic transformation. However, it remains unclear how <i>H. pylori</i> modulate DDR and autophagy in gastric carcinogenesis. Here we report that <i>H. pylori</i> infection promotes DNA damage via suppression of Rad51 expression through inhibition of autophagy and accumulation of p62 in gastric carcinogenesis. We find that <i>H. pylori</i> activated DNA damage pathway in concert with downregulation of repair protein Rad51 in gastric cells, C57BL/6 mice and Mongolian gerbils. In addition, autophagy was increased early and then decreased gradually during the duration of <i>H. pylori</i> infection in vitro in a CagA-dependent manner. Moreover, loss of autophagy led to promotion of DNA damage in <i>H. pylori</i>-infected cells. Furthermore, knockdown of autophagic substrate p62 upregulated Rad51 expression, and p62 promoted Rad51 ubiquitination via the direct interaction of its UBA domain. Finally, <i>H. pylori</i> infection was associated with elevated levels of p62 in gastric intestinal metaplasia and decreased levels of Rad51 in dysplasia compared to their <i>H. pylori-</i> counterparts. Our findings provide a novel mechanism into the linkage of <i>H. pylori</i> infection, autophagy, DNA damage and gastric tumorigenesis.