Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II

Yixuan Pan; Meiyang Liu; Chun Ruan; Mengyuan Peng; Min Hao; Qi Zhang; Jingdong Xue; Yanling Niu; Ningzhe Li; Haipeng Guan; Pei Wang; Mingqian Hu; Haitao Li; Wenjuan Wang; Juan Song; Yanhua Yao; Yimin Lao; Bing Li

doi:10.1038/s41594-024-01453-w

Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II

Nat Struct Mol Biol. 2025 Jan 8. doi: 10.1038/s41594-024-01453-w. Online ahead of print.

Authors

Yixuan Pan¹, Meiyang Liu^#¹, Chun Ruan^#², Mengyuan Peng^#¹, Min Hao¹, Qi Zhang¹, Jingdong Xue¹, Yanling Niu³, Ningzhe Li^{1

4}, Haipeng Guan⁵, Pei Wang⁵, Mingqian Hu¹, Haitao Li⁵, Wenjuan Wang⁶, Juan Song¹, Yanhua Yao¹, Yimin Lao⁷, Bing Li⁸

Affiliations

¹ Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Immunology and Microbiology, Shanghai Institute of Immunology and the Minister of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.
⁴ Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
⁵ State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, China.
⁶ Reproduction Medical Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
⁸ Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].

^# Contributed equally.

PMID: 39779918
DOI: 10.1038/s41594-024-01453-w

Abstract

The Rpd3S histone deacetylase complex has a crucial role in genomic integrity by deacetylating transcribed nucleosomes following RNA polymerase (Pol) II passage. Cryo-EM studies highlight the importance of asymmetrical Rco1-Eaf3 dimers in nucleosome binding, yet the interaction dynamics with nucleosomal substrates alongside elongating Pol II are poorly understood. Here we demonstrate the essential function of the Rco1 N-terminal intrinsically disordered region (IDR) in modulating Pol II association, in which K/R mutations within the Rco1 IDR impair interaction of Rpd3S with the C-terminal domain (CTD) of Rpb1, without affecting nucleosome recognition or complex integrity. We also identify the Rco1-PHD1 and Eaf3-CHD domains as crucial for specific binding to Ser5-phosphorylated CTD. The Rco1 IDR alleviates autoinhibition from its C terminus, facilitating PHD1-CHD engagement with phosphorylated CTD. Furthermore, we reveal a conserved mechanism by which asymmetrical Rco1-Eaf3 dimers coordinate nucleosome engagement and Pol II interaction, enhancing understanding of epigenetic complexes associated with transcriptional machinery.