NICHD

NEIL1

NEIL1, or Nei endonuclease VIII-like 1, is a human gene that encodes a DNA glycosylase enzyme involved in the base excision repair (BER) pathway. This enzyme plays a crucial role in maintaining genomic stability by recognizing and removing oxidized DNA bases, thereby preventing mutations and preserving the integrity of the genetic material.

Function

NEIL1 is part of the Fpg/Nei family of DNA glycosylases, which are responsible for the excision of oxidized purines and pyrimidines from DNA. The enzyme specifically recognizes and removes oxidized guanine lesions such as 8-oxoguanine, as well as other oxidized bases like formamidopyrimidines. After excision, NEIL1 cleaves the DNA backbone at the abasic site, creating a single-strand break that is further processed by other enzymes in the BER pathway.

Structure

The NEIL1 protein consists of several domains that contribute to its function. It contains a helix-hairpin-helix (HhH) motif, which is involved in DNA binding, and a catalytic domain that facilitates the glycosylase and lyase activities. The structure of NEIL1 allows it to recognize and bind to damaged DNA, positioning the oxidized base for excision.

Mechanism of Action

NEIL1 operates through a "base-flipping" mechanism, where the damaged base is flipped out of the DNA helix into the enzyme's active site. This allows NEIL1 to cleave the N-glycosidic bond between the base and the sugar-phosphate backbone, releasing the damaged base and leaving an abasic site. The enzyme then cleaves the DNA backbone at this site, generating a single-strand break with a 3'-phosphate and a 5'-deoxyribose phosphate.

Biological Significance

The activity of NEIL1 is essential for preventing the accumulation of oxidative DNA damage, which can lead to mutations and contribute to the development of cancer and other diseases. NEIL1 is expressed in various tissues, with higher levels in the liver, kidney, and brain, reflecting its importance in protecting cells from oxidative stress.

Clinical Implications

Mutations or polymorphisms in the NEIL1 gene have been associated with increased susceptibility to cancer and other age-related diseases. Understanding the role of NEIL1 in DNA repair pathways can provide insights into the mechanisms of carcinogenesis and aging, and may lead to the development of therapeutic strategies targeting DNA repair processes.

Research Directions

Current research on NEIL1 focuses on elucidating its role in the context of the entire DNA repair network, its interaction with other repair proteins, and its regulation under different physiological and pathological conditions. Studies are also exploring the potential of NEIL1 as a biomarker for oxidative stress and its involvement in neurodegenerative diseases.

Also see

• Base excision repair
• DNA glycosylase
• Oxidative DNA damage
• 8-oxoguanine
• Genomic stability