DNAJC9 integrates heat shock molecular chaperones into the histone chaperone network

Mol Cell. 2021 Jun 17;81(12):2533-2548.e9. doi: 10.1016/j.molcel.2021.03.041.

Colin M Hammond ¹, Hongyu Bao ², Ivo A Hendriks ³, Massimo Carraro ¹, Alberto García-Nieto ⁴, Yanhong Liu ², Nazaret Reverón-Gómez ¹, Christos Spanos ⁵, Liu Chen ², Juri Rappsilber ⁶, Michael L Nielsen ³, Dinshaw J Patel ⁷, Hongda Huang ⁸, Anja Groth ⁹

Affiliations

1 Novo Nordisk Foundation Center for Protein Research (CPR), University of Copenhagen, Copenhagen, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
2 Key Laboratory of Molecular Design for Plant Cell Factory of Guangdong Higher Education Institutes, Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
3 Novo Nordisk Foundation Center for Protein Research (CPR), University of Copenhagen, Copenhagen, Denmark.
4 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
5 Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
6 Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK; Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
7 Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected].
8 Key Laboratory of Molecular Design for Plant Cell Factory of Guangdong Higher Education Institutes, Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China. Electronic address: [email protected].
9 Novo Nordisk Foundation Center for Protein Research (CPR), University of Copenhagen, Copenhagen, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark. Electronic address: [email protected].

PMID: 33857403 DOI: 10.1016/j.molcel.2021.03.041

Abstract

From biosynthesis to assembly into nucleosomes, histones are handed through a cascade of histone chaperones, which shield histones from non-specific interactions. Whether mechanisms exist to safeguard the histone fold during histone chaperone handover events or to release trapped intermediates is unclear. Using structure-guided and functional proteomics, we identify and characterize a histone chaperone function of DNAJC9, a heat shock co-chaperone that promotes HSP70-mediated catalysis. We elucidate the structure of DNAJC9, in a histone H3-H4 co-chaperone complex with MCM2, revealing how this dual histone and heat shock co-chaperone binds histone substrates. We show that DNAJC9 recruits HSP70-type enzymes via its J domain to fold histone H3-H4 substrates: upstream in the histone supply chain, during replication- and transcription-coupled nucleosome assembly, and to clean up spurious interactions. With its dual functionality, DNAJC9 integrates ATP-resourced protein folding into the histone supply pathway to resolve aberrant intermediates throughout the dynamic lives of histones.

Keywords

DNAJC9; HSP40; HSP70; MCM2; TONSL; chromatin replication; heat shock co-chaperone; histone chaperone; nucleosome assembly; transcription.

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