Abstract
APE1 (DNA (apurinic/apyrimidinic site) endonuclease 1) is a key enzyme of one of the major DNA repair routes, the BER (base excision repair) pathway. APE1 fulfils additional functions, acting as a redox regulator of transcription factors and taking part in RNA metabolism. The mechanisms regulating APE1 are still being deciphered. Structurally, human APE1 consists of a well-characterized globular catalytic domain responsible for its endonuclease activity, preceded by a conformationally flexible N-terminal extension, acquired along evolution. This N-terminal tail appears to play a prominent role in the modulation of APE1 and probably in BER coordination. Thus, it is primarily involved in mediating APE1 localization, post-translational modifications, and protein–protein interactions, with all three factors jointly contributing to regulate the enzyme. In this review, recent insights on the regulatory role of the N-terminal region in several aspects of APE1 function are covered. In particular, interaction of this region with nucleophosmin (NPM1) might modulate certain APE1 activities, representing a paradigmatic example of the interconnection between various regulatory factors.
Highlights
While this review mostly focuses on how the DNA repair functions of APE1 are regulated, non-DNA repair activities of APE1 are briefly described as they are certainly important for cell function, and may be critical in specific cellular contexts
Acetylation might be seen as abrogating the role of the N-terminal tail, but it must be noted that acetylated APE1 does not behave exactly as a truncated version of the protein lacking the first 33 aminoacids
NPM1 stimulates incision of abasic DNA by APE1 in vitro [42,53]. This stimulatory effect could be explained by the fact that NPM1 favours specific binding of APE1 to abasic DNA, while competing with off-target associations [53]. Considered together, these results suggest that APE1 and NPM1 might cooperate in the base excision repair (BER) pathway (Figure 5): Through binding to the N-terminal tail of APE1, NPM1 would keep the enzyme in an open conformation, ready for selective and more efficient binding to abasic sites
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. One of the main DDR machineries is the base excision repair (BER) pathway [3,4] This pathway is essential in managing one of the most frequent types of DNA damage, i.e., mostly oxidative and alkylative, non-bulky base lesions. In addition to acting as a DNA repair protein, APE1 fulfils additional functions It was independently discovered as a redox factor regulating the DNA binding of several transcription factors involved in different growth signalling pathways [10]. We review the various cellular functions of APE1, discussing the possible regulatory operation of its N-terminal tail This evolutionarily acquired region, typical of eukaryotic APE1 homologues, may hold the clue to how the multifaceted functions are fine-tuned in this enzyme
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