The DNA Glycosylase NEIL2 Suppresses Fusobacterium-Infection-Induced Inflammation and DNA Damage in Colonic Epithelial Cells

Abstract

Colorectal cancer (CRC) is the third most prevalent cancer, while the majority (80–85%) of CRCs are sporadic and are microsatellite stable (MSS), and approximately 15–20% of them display microsatellite instability (MSI). Infection and chronic inflammation are known to induce DNA damage in host tissues and can lead to oncogenic transformation of cells, but the role of DNA repair proteins in microbe-associated CRCs remains unknown. Using CRC-associated microbes such as Fusobacterium nucleatum (Fn) in a coculture with murine and human enteroid-derived monolayers (EDMs), here, we show that, among all the key DNA repair proteins, NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated after Fn infection. Fn infection of NEIL2-null mouse-derived EDMs showed a significantly higher level of DNA damage, including double-strand breaks and inflammatory cytokines. Several CRC-associated microbes, but not the commensal bacteria, induced the accumulation of DNA damage in EDMs derived from a murine CRC model, and Fn had the most pronounced effect. An analysis of publicly available transcriptomic datasets showed that the downregulation of NEIL2 is often encountered in MSS compared to MSI CRCs. We conclude that the CRC-associated microbe Fn induced the downregulation of NEIL2 and consequent accumulation of DNA damage and played critical roles in the progression of CRCs.

Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19

“…Lung-organoid-derived monolayers were prepared using a modified protocol of GI-organoid-derived monolayers 44,[95][96][97] . Briefly, transwell inserts (6.5 mm diameter, 0.4 um pore size, Corning) were coated in Medium.…”

Role of the β-Catenin/REG Iα Axis in the Proliferation of Sessile Serrated Adenoma/Polyps Associated with Fusobacterium nucleatum

“…However, since SSA/P lesions are known to show high proliferative ability [5], we investigated the relationship between Fn positivity and proliferative ability in SSA/P lesions and subsequently clarified that Fn-positive lesions had higher proliferative ability than Fn-negative lesions. In addition to proliferative ability, Fn infection appears to accelerate inflammation and DNA damage in colonic epithelial cells, and those accelerations may be regulated by a specific DNA glycosylase [35]. These findings suggest that not only cell proliferation, but also inflammation-associated DNA damage may be a key to understand the effect of Fn infection on the progression of malignant potential in SSA/P lesions.…”

Intrapulmonary administration of purified NEIL2 abrogates NF-κB–mediated inflammation

“…In recent years, several studies have suggested that the oxidative DNA damage-induced cellular DNA damage response (DDR) can initiate an immune response that directly activates a variety of transcription factors, such as NF-κB, STAT and interferon regulatory factors (11)(12)(13)(14)(15). Additionally, several groups, including ours, have reported non-J o u r n a l P r e -p r o o f canonical roles of the BER proteins, including Poly [ADP-ribose] polymerase 1 (PARP1), 8-Oxoguanine glycosylase (OGG1) and Nei Like DNA Glycosylase 2 (NEIL2), in innate immunity (13,(16)(17)(18)(19). Our recent studies have demonstrated that 8-oxoG-bound OGG1 in the promoters of proinflammatory genes facilitates NF-κB recruitment to target gene promoters and enhances their expression (20,21).…”