The Pivotal Role of DNA Repair in Infection Mediated-Inflammation and Cancer

Abstract

Pathogenic and commensal microbes induce various levels of inflammation and metabolic disease in the host. Inflammation caused by infection leads to increased production of reactive oxygen species (ROS) and subsequent oxidative DNA damage. These in turn cause further inflammation and exacerbation of DNA damage, and pose a risk for cancer development. Helicobacter pylori-mediated inflammation has been implicated in gastric cancer in many previously established studies, and Fusobacterium nucleatum presence has been observed with greater intensity in colorectal cancer patients. Despite ambiguity in the exact mechanism, infection-mediated inflammation may have a link to cancer development through an accumulation of potentially mutagenic DNA damage in surrounding cells. The multiple DNA repair pathways such as base excision, nucleotide excision, and mismatch repair that are employed by cells are vital in the abatement of accumulated mutations that can lead to carcinogenesis. For this reason, understanding the role of DNA repair as an important cellular mechanism in combatting the development of cancer will be essential to characterizing the effect of infection on DNA repair proteins and to identifying early cancer biomarkers that may be targeted for cancer therapies and treatments.

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

“…One of the major sources of oxidative DNA damage in the colon is the disbalance of bacterial communities. Bacterial infection-induced inflammation leads to the generation of reactive oxygen species (ROS) that can result in oxidative damage, which is more prominent, especially with bacteria causing chronic infection (24). Bacterial species that play a role in the pathogenesis of CRC include Bacteroides fragilis, Helicobacter pylori, Escherichia coli, Enterococcus faecalis, and Clostridium septicum (71,72).…”

“…E. coli Nei-like (NEIL1-3) proteins are a distinct family of DNA glycosylases that remove both purines and pyrimidines. They initiate the excision of lesions present in a single-stranded region, a replication fork, or transcription bubble mimic (23)(24)(25)(26)(27)(28). Reduced expression of NEIL1, NEIL2, and elevated expression of NEIL3 is involved in the progression of several types of cancer via their association with the somatic mutation load (29).…”

Comparative analysis of macrophage post-translational modifications during intracellular bacterial pathogen infection

“…Like TBK1, ATM and CHK2 were also predicted to be upregulated in all three IBP infections, both of which are activated under conditions of DNA damage. Activation of the host DNA damage could be the result of increased oxidative stress generated by NADPH oxidase (Sahan et al, 2018), which itself was ubiquitylated during infection ( Figure 1 E, CY24B). Surprisingly, several cyclindependent kinases (CDK1, CDK2, CDK4, CDK7) were downregulated with all three IBPs, indicating that infection led to cell cycle arrest.…”

NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells

“…Generally, the bacterial infection-induced inflammation leads to the generation of reactive oxygen species (ROS) that in turn cause oxidative genome damage in the host cells. Without timely repair, the mutagenic DNA lesions can cause several pathologies, including cancer (10)(11)(12)(13). Oxidized DNA bases are primarily repaired via the DNA Base Excision Repair (BER) pathway (14,15).…”

“…Several other groups and we then found that mammalian cells possess a new family of DNA glycosylases, and named them E. coli Nei-like (NEIL1-3). NEILs are capable of removing both purines and pyrimidines; however, these DGs are unique with respect to DNA damage recognition, as OGG1 and NTH1 remove the damage from duplex DNA, whereas NEILs prefer to initiate excision of lesions that are located in a single-stranded region, a replication fork or transcription bubble mimic (13,23,24). Indeed, it was found that NEIL1 and NEIL3 are mostly involved in repairing the damage in replicating cells, and NEIL2 primarily removes the oxidized DNA bases from the transcribed regions (24).…”