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

Abstract

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.

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

“…Indeed, in addition to direct inhibitors of APE1 nuclease activities, inhibitors against other functions of APE1 may also be clinically valuable. Considering the complex role of APE1, exploring allosteric modes of inhibition, such as disrupting vital interactions between APE1 and other cellular protein partners, might be an alternative option [118,201]. For example, we demonstrated that the molecular association with NPM1 modulates the endonuclease activity of APE1 [118].…”