Environmental toxins and toxicants can produce conditions of oxidative stress resulting in the formation of reactive oxygen and nitrogen species (RONS). The presence of RONS causes the oxidation of all four conical bases creating a diverse number of lesions including: thymine glycol (Tg), 5-hydroxycytosine (5-OHC), 5-hydroxyuracil (5-OHU), dihydrothymine (DHT), the formamidopyridines (FapyA and FapyG), guanidinohydantoin (Gh), and spiriminodihydatoin (Sp). The DNA glycosylase, NEIL1, is able to excise all of these lesions from several DNA contexts. Additionally, the pre-mRNA of NEIL1 is subject to modification by the Adenosine Deaminase Acting on RNA (ADAR1) that leads to a recoding event that converts a lysine to arginine in the lesion recognition loop of NEIL1.  This leads to the presence of two isoforms of NEIL1 under different cellular conditions.  Notably, the two isoforms display different enzymatic properties on Tg, where the unedited (K242) isoform showed a significantly faster rate of excision compared to edited NEIL1 (R242). We have performed detailed examinations of lesion processing by the two NEIL1 isoforms on a large number of substrates, and many interesting trends have emerged.  In general, unedited NEIL1 demonstrates better excision of oxidized pyrimidines than the edited isoform. The impact of RNA editing on NEIL1 activity suggests a unique regulatory mechanism for DNA repair.<br/>

DNA glycosylase NEIL1 demonstrates lesion specificity from RNA editing

2019 Fall National Meeting

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