APE1 interacts with the nuclear exosome complex protein MTR4 and is involved in cisplatin- and 5-fluorouracil-induced RNA damage response.

Autor: Codrich M; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Italy., Degrassi M; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Italy., Malfatti MC; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Italy., Antoniali G; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Italy., Gorassini A; Department of Humanities and Cultural Heritage, University of Udine, Italy., Ayyildiz D; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Italy., De Marco R; Department of Agricultural, Food, Environmental and Animal Sciences, University of Udine, Italy., Verardo G; Department of Agricultural, Food, Environmental and Animal Sciences, University of Udine, Italy., Tell G; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Italy.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2023 Apr; Vol. 290 (7), pp. 1740-1764. Date of Electronic Publication: 2022 Nov 15.
DOI: 10.1111/febs.16671
Abstrakt: The nuclear RNA surveillance mechanism is essential for cancer cell survival and is ensured by the RNA nuclear exosome including some co-factors, such as the RNA helicase MTR4. Recent studies suggest an involvement of DNA repair proteins such as apurinic/apyrimidinic (AP) endodeoxyribonuclease 1 (APE1), a major endodeoxyribonuclease of Base Excision Repair (BER), in RNA metabolism and RNA decay of oxidized and abasic RNA. Cisplatin (CDDP) and 5-fluorouracil (5-FU) are commonly used for the treatment of solid tumours. Whether APE1 is involved in the elimination of CDDP- or 5-FU-damaged RNA is unknown, as is its possible interaction with the nuclear exosome complex. Here, by using different human cancer cell models, we demonstrated that: (a) APE1 is involved in the elimination of damaged-RNA, upon CDDP- and 5-FU-treatments, in a MTR4-independent manner; (b) the interaction between APE1 and MTR4 is stimulated by CDDP- and 5-FU-treatments through lysine residues in the APE1 N-terminal region and is, in part, mediated by nucleic acids and (c) APE1- and MTR4-depletion lead to the generation of R-loop formation causing the activation of the DNA damage response (DDR) pathway through the ATM-p53-p21 axis. Our data demonstrate a role of MTR4 in DDR underpinning the function of APE1 in controlling the RNA quality upon genotoxic treatments with possible implications in chemoresistance.
(© 2022 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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