RBBP6 anchors pre-mRNA 3' end processing to nuclear speckles for efficient gene expression

Yoseop Yoon; Elodie Bournique; Lindsey V Soles; Hong Yin; Hsu-Feng Chu; Christopher Yin; Yinyin Zhuang; Xiangyang Liu; Liang Liu; Joshua Jeong; Clinton Yu; Marielle Valdez; Lusong Tian; Lan Huang; Xiaoyu Shi; Georg Seelig; Fangyuan Ding; Liang Tong; Rémi Buisson; Yongsheng Shi

doi:10.1016/j.molcel.2024.12.016

RBBP6 anchors pre-mRNA 3' end processing to nuclear speckles for efficient gene expression

Mol Cell. 2025 Jan 8:S1097-2765(24)01033-5. doi: 10.1016/j.molcel.2024.12.016. Online ahead of print.

Authors

Yoseop Yoon¹, Elodie Bournique², Lindsey V Soles¹, Hong Yin³, Hsu-Feng Chu⁴, Christopher Yin⁵, Yinyin Zhuang⁶, Xiangyang Liu⁴, Liang Liu¹, Joshua Jeong¹, Clinton Yu⁷, Marielle Valdez¹, Lusong Tian¹, Lan Huang⁷, Xiaoyu Shi⁸, Georg Seelig⁹, Fangyuan Ding³, Liang Tong⁴, Rémi Buisson², Yongsheng Shi¹⁰

Affiliations

¹ Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
² Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
³ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA.
⁴ Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
⁵ Department of Electrical and Computer Engineering, University of Washington, Seattle, Seattle, WA 98195, USA.
⁶ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
⁷ Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA.
⁸ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
⁹ Department of Electrical and Computer Engineering, University of Washington, Seattle, Seattle, WA 98195, USA; Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, Seattle, WA 98195, USA.
¹⁰ Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: [email protected].

PMID: 39798570
DOI: 10.1016/j.molcel.2024.12.016

Abstract

Pre-mRNA 3' processing is an integral step in mRNA biogenesis. However, where this process occurs in the nucleus remains unknown. Here, we demonstrate that nuclear speckles (NSs), membraneless organelles enriched with splicing factors, are major sites for pre-mRNA 3' processing in human cells. We show that the essential pre-mRNA 3' processing factor retinoblastoma-binding protein 6 (RBBP6) associates strongly with NSs via its C-terminal intrinsically disordered region (IDR). Importantly, although the conserved N-terminal domain (NTD) of RBBP6 is sufficient for pre-mRNA 3' processing in vitro, its IDR-mediated association with NSs is required for efficient pre-mRNA 3' processing in cells. Through proximity labeling analyses, we provide evidence that pre-mRNA 3' processing for over 50% of genes occurs near NSs. We propose that NSs serve as hubs for RNA polymerase II transcription, pre-mRNA splicing, and 3' processing, thereby enhancing the efficiency and coordination of different gene expression steps.

Keywords: biomolecular condensate; cleavage and polyadenylation; gene expression; intrinsically disordered region; membraneless organelle; nuclear speckle; phase separation; pre-mRNA 3′ end processing; transcription termination.