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Structural basis of SIRT7 nucleosome engagement and substrate specificity

Author

Listed:
  • Carlos Moreno-Yruela

    (EPFL)

  • Babatunde E. Ekundayo

    (EPFL
    University of Lausanne)

  • Polina N. Foteva

    (EPFL)

  • Dongchun Ni

    (EPFL
    University of Lausanne)

  • Esther Calvino-Sanles

    (EPFL)

  • Henning Stahlberg

    (EPFL
    University of Lausanne)

  • Beat Fierz

    (EPFL)

Abstract

Chromatin-modifying enzymes target distinct residues within histones to finetune gene expression profiles. SIRT7 is an NAD+-dependent deacylase often deregulated in cancer, which deacetylates either H3 lysine 36 (H3K36) or H3K18 with high specificity within nucleosomes. Here, we report structures of nucleosome-bound SIRT7, and uncover the structural basis of its specificity towards H3K36 and K18 deacylation, combining a mechanism-based cross-linking strategy, cryo-EM, and enzymatic and cellular assays. We show that the SIRT7 N-terminus represents a unique, extended nucleosome-binding domain, reaching across the nucleosomal surface to the acidic patch. The catalytic domain binds at the H3-tail exit site, engaging both DNA gyres of the nucleosome. Contacting H3K36 versus H3K18 requires a change in binding pose, and results in structural changes in both SIRT7 and the nucleosome. These structures reveal the basis of lysine specificity, allowing us to engineer SIRT7 towards enhanced H3K18ac selectivity, and provides a basis for small molecule modulator development.

Suggested Citation

  • Carlos Moreno-Yruela & Babatunde E. Ekundayo & Polina N. Foteva & Dongchun Ni & Esther Calvino-Sanles & Henning Stahlberg & Beat Fierz, 2025. "Structural basis of SIRT7 nucleosome engagement and substrate specificity," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56529-y
    DOI: 10.1038/s41467-025-56529-y
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    References listed on IDEAS

    as
    1. Matthew F. Barber & Eriko Michishita-Kioi & Yuanxin Xi & Luisa Tasselli & Mitomu Kioi & Zarmik Moqtaderi & Ruth I. Tennen & Silvana Paredes & Nicolas L. Young & Kaifu Chen & Kevin Struhl & Benjamin A., 2012. "SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation," Nature, Nature, vol. 487(7405), pages 114-118, July.
    2. Lei Li & Lan Shi & Shangda Yang & Ruorong Yan & Di Zhang & Jianguo Yang & Lin He & Wanjin Li & Xia Yi & Luyang Sun & Jing Liang & Zhongyi Cheng & Lei Shi & Yongfeng Shang & Wenhua Yu, 2016. "SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability," Nature Communications, Nature, vol. 7(1), pages 1-17, November.
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