Volume 33, No 10, Oct 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 10, October 2023: 790-801   |  Open Access

ORIGINAL ARTICLES

Structural basis of nucleosome deacetylation and DNA linker tightening by Rpd3S histone deacetylase complex

Shuqi Dong^1,2,† , Huadong Li^3,† , Meilin Wang^3,† , Nadia Rasheed^1,3,† , Binqian Zou¹ , Xijie Gao^3,4 , Jiali Guan^1,2 , Weijie Li⁵ , Jiale Zhang^1,2 , Chi Wang⁶ , Ningkun Zhou¹ , Xue Shi^1,2 , Mei Li⁷ , Min Zhou⁷ , Junfeng Huang¹ , He Li⁴ , Ying Zhang⁵ , Koon Ho Wong³ , Xiaofei Zhang^1,4 , William Chong Hang Chao^3,* , Jun He^1,4,*

¹CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong–Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
²University of Chinese Academy of Sciences, Beijing, China
³Faculty of Health Sciences, University of Macau, Macau SAR, China
⁴Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
⁵Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China
⁶School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
⁷Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong, China
^†These authors contributed equally: Shuqi Dong, Huadong Li, Meilin Wang, Nadia Rasheed
Correspondence: William Chong Hang Chao(williamchao@um.edu.mo)Jun He(he_jun@gibh.ac.cn)

In Saccharomyces cerevisiae, cryptic transcription at the coding region is prevented by the activity of Sin3 histone deacetylase (HDAC) complex Rpd3S, which is carried by the transcribing RNA polymerase II (RNAPII) to deacetylate and stabilize chromatin. Despite its fundamental importance, the mechanisms by which Rpd3S deacetylates nucleosomes and regulates chromatin dynamics remain elusive. Here, we determined several cryo-EM structures of Rpd3S in complex with nucleosome core particles (NCPs), including the H3/H4 deacetylation states, the alternative deacetylation state, the linker tightening state, and a state in which Rpd3S co-exists with the Hho1 linker histone on NCP. These structures suggest that Rpd3S utilizes a conserved Sin3 basic surface to navigate through the nucleosomal DNA, guided by its interactions with H3K36 methylation and the extra-nucleosomal DNA linkers, to target acetylated H3K9 and sample other histone tails. Furthermore, our structures illustrate that Rpd3S reconfigures the DNA linkers and acts in concert with Hho1 to engage the NCP, potentially unraveling how Rpd3S and Hho1 work in tandem for gene silencing.

https://doi.org/10.1038/s41422-023-00869-1

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