mRNA export factors store nascent transcripts within nuclear speckles as an adaptive response to transient global inhibition of transcription

Williams, TD; Michalak, EM; Carey, KT; Lam, EYN; Anderson, A; Griesbach, E; Chan, YC; Papasaikas, P; Tan, VWT; Ngo, L; MacPherson, L; Gilan, O; Rucinski, A; Rutkowska-Klute, A; Zinn, N; Grandi, P; Bantscheff, M; Prinjha, RK; Dawson, SJ; Chao, JA; Wickramasinghe, VO; Dawson, MA

Author(s): Williams, TD; Michalak, EM; Carey, KT; Lam, EYN; Anderson, A; Griesbach, E; Chan, YC; Papasaikas, P; Tan, VWT; Ngo, L; MacPherson, L; Gilan, O; Rucinski, A; Rutkowska-Klute, A; Zinn, N; Grandi, P; Bantscheff, M; Prinjha, RK; Dawson, SJ; Chao, JA; Wickramasinghe, VO; Dawson, MA;
Details: Publication Year 2025-01-02,Volume 85,Issue #1,Page 117-131
Journal Title: Molecular Cell
Publication Type: Research article
Abstract: Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity, highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output but also markedly impair mRNA transcript localization and nuclear export. We demonstrate that retention of newly transcribed mRNA in nuclear speckles is an adaptive response to chemically distinct transcriptional inhibitors. Retained transcripts are fully processed and accumulate in proportion to the expression level of the genes from which they emanate. The TREX mRNA export complex plays an integral role in directing nascent transcripts to nuclear speckles where they are bound to NXF1, protected from degradation, and poised for rapid export following re-initiation of transcription. Our findings provide new insights into the crosstalk between transcription and mRNA export with important implications for drugs aiming to inhibit transcription for therapeutic gain.
Publisher: Cell Press
Keywords: *RNA, Messenger/genetics/metabolism; Humans; *Active Transport, Cell Nucleus; *Transcription, Genetic; *Cell Nucleus/metabolism/genetics; *RNA Transport; HeLa Cells; Nucleocytoplasmic Transport Proteins/metabolism/genetics; RNA-Binding Proteins/metabolism/genetics; BET degrader; Drb; Nxf1; Nuclear export; Trex; epigenetic drugs; mRNA localisation; nuclear speckles; transcription
Department(s): Laboratory Research; Haematology
Publisher's Version: https://doi.org/10.1016/j.molcel.2024.12.008
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-23 02:18:59

Last Modified: 2025-01-23 02:30:24