Neil1Edit
Neil1, or Nei-like 1 DNA glycosylase, is an enzyme that plays a key role in maintaining genome integrity by repairing oxidative DNA damage. As a member of the Nei-like family of DNA glycosylases, it sits alongside NEIL2 and NEIL3 as part of a conserved repair system that guards the genome against lesions produced by reactive oxygen species and other oxidants. In humans, the NEIL1 gene encodes the enzyme that operates in both the nucleus and mitochondria, enabling repair of damage in nuclear DNA and mitochondrial DNA alike. The catalytic action of NEIL1 initiates the base excision repair (BER) pathway, a central mechanism by which cells fix small, chemically damaged bases and prevent mutations that could contribute to disease over time. NEIL1 functions as a bifunctional glycosylase/lyase (AP lyase), excising damaged bases and nicking the DNA backbone to prepare the site for downstream processing by enzymes such as APE1 in the BER cascade.
Structure and function
NEIL1 is part of the HhH-GPD superfamily of DNA glycosylases, enzymes that locate and remove damaged bases from DNA. The protein’s structure supports recognition of a variety of oxidized bases and positions the DNA for cleavage. Beyond its catalytic activity, NEIL1 can coordinate with replication and repair machinery, underscoring a role at the interface of DNA repair and replication. By operating in both the nucleus and mitochondria, NEIL1 helps safeguard the genome across compartments that experience different oxidative stresses.
Substrate recognition
NEIL1 exhibits a broad but specific substrate range among oxidized DNA lesions. It efficiently removes oxidized pyrimidines such as thymine glycol and 5,6-dihydrouracil, as well as oxidized purines including formamidopyrimidines (FapyA and FapyG). The enzyme’s activity is particularly relevant when DNA is exposed during replication or transcription, where strands temporarily become more susceptible to oxidative damage. The exact spectrum of substrates can vary with conditions and species, but NEIL1 consistently contributes to the repair of lesions that are not always efficiently handled by other glycosylases.
Localization and interactions
The dual localization of NEIL1 to both the nucleus and mitochondria reflects the need to repair DNA in different cellular compartments. In the nucleus, NEIL1 can interact with components of the replication machinery, such as PCNA, to help repair lesions that arise during DNA synthesis. It also interfaces with other BER factors like RPA and XRCC1 to coordinate lesion recognition, excision, and strand break processing. In mitochondria, NEIL1 helps protect mtDNA from oxidative damage that can disrupt energy production and cell viability.
Genetic and evolutionary context
The NEIL1 gene is conserved across a wide range of organisms, underscoring the ancient and essential nature of oxidative base repair. In humans, NEIL1 is one of several Nei-like glycosylases that together cover a broad spectrum of oxidative lesions. The family’s diversification into NEIL1, NEIL2, and NEIL3 reflects specialization for different DNA contexts, such as single-stranded regions or different cellular compartments, while preserving the core strategy of removing damaged bases and creating a site for repair.
Biological significance and disease associations
Repairing oxidative DNA damage is fundamental to preventing mutations that can accumulate with age and contribute to various diseases. NEIL1’s proper function supports genome stability in tissues with high metabolic activity and during DNA replication. Experimental models, including cell culture and animal studies, show that reduced NEIL1 activity or altered expression can increase sensitivity to oxidative stress and elevate mutation rates. Human studies have explored associations between NEIL1 polymorphisms and disease risk, including cancer susceptibility and neurodegenerative conditions, though results across studies have often been mixed and require careful interpretation. The prevailing view is that NEIL1 operates as part of a robust, redundant BER network, and its impact may depend on genetic context and environmental exposure to oxidative stress.
Research and perspectives
Ongoing work seeks to clarify NEIL1’s substrate preferences under physiological conditions, its precise regulation during the cell cycle, and how its interactions with replication and repair proteins influence repair outcomes. Advances in structural biology, single-molecule studies, and genome-wide analyses continue to illuminate how NEIL1 contributes to maintaining genome stability, how it cooperates with other BER factors, and how naturally occurring genetic variation in NEIL1 might affect human health.