Apurinic/Apyrimidinic Endodeoxyribonuclease 1 modulates RNA G-quadruplex folding of miR-92b and controls its expression in cancer cells.

Autor:	Bellina A; Laboratory of Molecular Biology and DNA repair, Department of Medicine, University of Udine, Udine 33100, Italy., Malfatti MC; Laboratory of Molecular Biology and DNA repair, Department of Medicine, University of Udine, Udine 33100, Italy.; Liver Cancer Unit, Fondazione Italiana Fegato-Organizzazione Non Lucrativa di Utilità Sociale, Basovizza 34149, Italy., Salgado G; Department of Life Sciences and Technology for Health, ARNA laboratory, INSERM U1212, CNRS, UMR 5320, University of Bordeaux, Bordeaux F-33076, France., Fleming AM; Department of Chemistry, University of Utah, Salt Lake City, UT 84112-0850., Antoniali G; Laboratory of Molecular Biology and DNA repair, Department of Medicine, University of Udine, Udine 33100, Italy., Othman Z; Department of Life Sciences and Technology for Health, ARNA laboratory, INSERM U1212, CNRS, UMR 5320, University of Bordeaux, Bordeaux F-33076, France., Gualandi N; Laboratory of Molecular Biology and DNA repair, Department of Medicine, University of Udine, Udine 33100, Italy., La Manna S; STARS lab (Structure Activity Relationship Synthesis and Spectroscopy), Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy., Marasco D; STARS lab (Structure Activity Relationship Synthesis and Spectroscopy), Department of Pharmacy, University of Naples 'Federico II', Naples 80131, Italy., Dassi E; Laboratory of RNA Regulatory Networks, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento 38123, Italy., Burrows CJ; Department of Chemistry, University of Utah, Salt Lake City, UT 84112-0850., Tell G; Laboratory of Molecular Biology and DNA repair, Department of Medicine, University of Udine, Udine 33100, Italy.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Nov 12; Vol. 121 (46), pp. e2317861121. Date of Electronic Publication: 2024 Nov 04.
DOI:	10.1073/pnas.2317861121
Abstrakt:	In the last decade, several novel functions of the mammalian Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) have been discovered, going far beyond its canonical function as DNA repair enzyme and unveiling its potential roles in cancer development. Indeed, it was shown to be involved in DNA G-quadruplex biology and RNA metabolism, most importantly in the miRNA maturation pathway and the decay of oxidized or abasic miRNAs during oxidative stress conditions. In recent years, several noncanonical pathways of miRNA biogenesis have emerged, with a specific focus on guanosine-rich precursors that can form RNA G-quadruplex (rG4) structures. Here, we show that several miRNA precursors, dysregulated upon APE1 depletion, contain an rG4 motif and that their corresponding target genes are up-regulated after APE1 depletion. We also demonstrate, both by in vitro assays and by using different cancer cell lines, that APE1 can modulate the folding of an rG4 structure contained in pre-miR-92b, with a mechanism strictly dependent on lysine residues present in its N-terminal disordered region. Furthermore, APE1 cellular depletion alters the maturation process of miR-92b, mainly affecting the shuttling between the nucleus and cytosol. Bioinformatic analysis of APE1-regulated rG4-containing miRNAs supports the relevance of our findings in cancer biology. Specifically, these miRNAs exhibit high prognostic significance in lung, cervical, and liver tumors, as suggested by their involvement in several cancer-related pathways. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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