DNA glycosylase NEIL2 prevents Fusobacterium-mediated inflammation and DNA damage in colonic epithelial cells

Abstract

Colorectal cancer (CRC) is the third most prevalent and deadly cancer. Approximately, 15-20 % of CRCs display microsatellite instability (MSI); however, the majority (80-85%) of cases are sporadic and known as microsatellite stable (MSS). Several recent studies indicated that infection and uncontrolled inflammation initiate DNA damage and lead to cancer progression. One of the major microbes, Fusobacterium nucleatum (Fn) is highly associated with CRC, but the role of DNA repair in microbe-associated CRC has been largely unknown. Here we show that NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated among all the key DNA repair proteins involved in various DNA repair pathways, after infection of Fn with stem-cell-based enteroid-derived monolayers (EDMs) of murine and human healthy subjects. Furthermore, following Fn infection, NEIL2-null mouse-derived EDMs showed significantly higher level of DNA damage, including double strand breaks, and inflammatory cytokines.. Murine CRC model also showed downregulation of the NEIL2 transcript and accumulation of DNA damage. Importantly, analysis of publicly available transcriptomic data showed that the downregulation of NEIL2 is specific for MSS compared to MSI CRCs. We thus conclude that the pathogenic bacterial infection-induced downregulation of NEIL2, and consequent accumulation of DNA damage, play critical roles in the progression of CRC.