DNA repair and disease: insights from the human DNA glycosylase NEIL family

Abstract

The base excision repair pathway protects DNA from base damage via oxidation, deamination, alkylation and methylation. DNA glycosylases are key enzymes that recognize damaged bases in a lesion-specific manner and initiate the base excision repair process. Among these, the endonuclease VIII-like 1–3 (NEIL1–3) family, which is found in mammalian genomes, is a homolog of bacterial DNA glycosylases known as Fpg/Nei. NEIL enzymes have similar structures and substrates but with slight differences. When repair proteins are impaired, the accumulation of damaged bases can lead to increased genomic instability, which is implicated in various pathologies, including cancer and neurodegeneration. Notably, mutations in these proteins also influence a range of other diseases and inflammation. This review focuses on the influence of the NEIL family on human health across different organ systems. Investigating the relationship between NEIL mutations and diseases can improve our understanding of how these enzymes affect the human body. This information is crucial for understanding the basic mechanisms of DNA repair and enabling the development of novel inhibitors or gene therapies that target only these enzymes. Understanding the role of the NEIL family provides insights into novel therapies and improves our ability to combat genetic diseases. The base excision repair pathway is crucial for fixing DNA damage, including oxidative base lesions, and maintaining genetic stability. This article reviews the role of NEIL enzymes, which are part of the base excision repair pathway, in various diseases. NEIL enzymes help to repair damaged DNA by removing faulty bases caused by oxidative or alkylation damage. The study highlights the diverse roles of NEIL1, NEIL2 and NEIL3 enzymes in various organ systems and diseases. The researchers found that NEIL1 is broadly associated with the nervous and cardiovascular systems, and uniquely affects the integumentary system and liver, while the functions of NEIL2 are primarily concentrated in the immune and respiratory systems and are specifically associated with bacterial infections of the stomach and large intestine. NEIL3 is linked to the cardiovascular and immune systems, but unlike other NEILs, it shows no independent organ-specific effects. This review also shows that these enzymes play roles in brain health, immune response and skin protection. These findings suggest that understanding NEIL enzymes can lead to better treatments for diseases related to DNA damage by enabling targeted therapies, such as small-molecule modulators, and guiding research to enhance DNA repair in specific diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.