Bibliografisk note

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We thank laboratory technicians Hanne Jørgensen, Ulla Birk Henriksen, and Bente Flügel for their excellent technical assistance. We also thank the Brødrene Hartmanns Fond for providing financial support for Knud Larsen.

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Yeo et al. [24] discovered that a codon shift from AAA (Lys) to AIA (Arg), as a result of A-to-I RNA editing of the NEIL1 pre-mRNA, leads to a functional variant with markedly different substrate specificity. The Arg-242 variant excises thymine glycol (Tg) 30 times slower than the Lys-242 variant, while Gh and Sp are excised approximately three and two times faster, respectively [24]. These findings were supported by Minko et al. [27], who showed that edited NEIL1 excises 5-hydroxycytosine (5-OHC) five times as efficiently but observed no significant difference in excision for the formanidopyrimidines FaPyA and FaPyG when all lesions (and Tg) were present in the same high-molecular weight genomic DNA. The difference in substrate specificity for Tg between the two NEIL1 isoforms seems to be associated with base excision rather than substrate recognition, as binding affinities are similar [27]. The codon for K242 may also be edited at the third adenosine position (AAA to AAI), but this does not result in an amino acid substitution. This change in substrate specificity may be important for regulation of NEIL1 activity throughout cell and tissues, as the properties of NEIL1 suggest that different repair pathways may be initiated dependent on the specific circumstances and lesions encountered. It is possible that editing is more prevalent when hydantoin lesions are abundant and suppressed when Tg is abundant [24]. Yeo et al. [24] demonstrated that editing of the second adenosine was primarily executed by ADAR1 and, by extension, that NEIL1 could be extracellularly regulated by IFN-α. ADAR1–transcription is stimulated by IFN-α for induction in T-lymphocytes and macrophages and, as such, NEIL1 is predicted to undergo more editing during inflammation. However, this association may play a role in the changes of number and type of mutations in lobular breast cancer (or other tumors) with over-expressed ADAR1, as prolonged hyper-editing of NEIL1 may lead to insufficient repair of NEIL1 substrates [24]. In multiple myeloma cell lines, the lines expressing Agr242 have been shown to display higher growth rates, enhanced cell cycle progression, and upregulation of markers in DNA double-stranded breaks [27]. Recently, Yeo et al. [55] demonstrated that both unedited and edited isoforms of NEIL1 catalyze low levels of 5-hydroxyuracil (5-OHU) excision in single-stranded, bubble, and bulge DNA contexts and in duplex DNA base paired with A. In addition, Yeo et al. [55] showed that removal of 5-OHU in base pairs with G, T, and C was faster and proceeded to a greater overall extent with unedited than with edited NEIL1. Yeo et al. [55] also reported that edited NEIL1 exhibits higher affinity for 5-OHU:G and 5-OHU:C duplexes than unedited NEIL1.

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