NEIL1 Recoding due to RNA Editing Impacts Lesion-Specific Recognition and Excision

Area of Science:

• Molecular Biology
• Biochemistry
• Genetics

Background:

• A-to-I RNA editing is common in humans but rare in coding regions outside the nervous system.
• The base excision DNA repair enzyme NEIL1 is unusually targeted for recoding by ADAR1.
• This editing converts lysine to arginine in NEIL1's lesion recognition loop, altering its substrate specificity.

Purpose of the Study:

• To investigate how A-to-I RNA editing affects NEIL1's DNA repair activity.
• To understand the chemical and structural features influencing isoform-specific repair of oxidatively damaged DNA bases.

Main Methods:

• Enzyme activity assays comparing unedited (UE) and edited (Ed) NEIL1 isoforms.
• Evaluation of repair efficiency on various oxidatively modified DNA bases.
• Gas-phase calculations to analyze base lesion properties.

Main Results:

• UE NEIL1 shows higher activity against oxidized pyrimidines (e.g., thymine glycol, uracil glycol).
• Ed NEIL1 is more efficient at removing 5-hydroxycytosine and guanidinohydantoin.
• Excision rates correlate with base tautomer stability and proton affinity.

Conclusions:

• NEIL1 editing creates functional isoforms with distinct substrate specificities.
• Tautomerization and N3 protonation are key in NEIL1's catalytic mechanism for pyrimidine lesions.
• Complex NEIL1 activity suggests roles in DNA repair and epigenetic regulation.