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

Ibrahim M Sayed,Debashis Sahoo,Anirban Chakraborty,Aditi Sharma,Wendy Jia Men Huang,Pradipta Ghosh,Soumita Das,Amer Ali Abd El-Hafeez,Ayse Z Sahan,Tapas K Hazra

doi:10.3390/cells9091980

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.

Highlights

Colorectal cancer (CRC) is the third-most prevalent cancer and the fourth-most frequent cause of cancer death in the USA and around the world, according to GLOBOCAN 2018 data and the AmericanCells 2020, 9, 1980; doi:10.3390/cells9091980 www.mdpi.com/journal/cellsCancer Society, 2017 [1]
When comparing the level of oxidized base adducts produced from different colon cancer pathogens to untreated enteroid-derived monolayers (EDMs), we found that Fusobacterium nucleatum (Fn) infection had the highest oxidative DNA
When comparing the level of oxidized base adducts produced from different colon cancer pathogens to untreated EDMs, we found that Fn infection had the highest oxidative DNA damage levels, followed by H. pylori and E. coli NC101 (Figure 6B)

Summary

Introduction

Colorectal cancer (CRC) is the third-most prevalent cancer and the fourth-most frequent cause of cancer death in the USA and around the world, according to GLOBOCAN 2018 data and the AmericanCells 2020, 9, 1980; doi:10.3390/cells9091980 www.mdpi.com/journal/cellsCancer Society, 2017 [1]. For the genetic subtype of CRC, the presence or absence of mutations in the DNA mismatch repair system is well-documented [9]. This hypermutable subtype or deficient mismatch repair (dMMR) system is responsible for only 15% of CRCs, which is known as microsatellite instable (MSI) CRC [10]. The defect in the MMR pathway leads to MSI, and it is a common etiologic factor for the development of CRC, such as hereditary non-polyposis colon cancer (HNPCC), known as Lynch syndrome [11].

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