DNAJC9 integrates heat shock molecular chaperones into the histone chaperone network

Colin M Hammond,Hongyu Bao,Ivo A Hendriks,Massimo Carraro,Alberto García-Nieto,Yanhong Liu,Nazaret Reverón-Gómez,Christos Spanos,Liu Chen,Juri Rappsilber,Michael L Nielsen,Dinshaw J Patel,Hongda Huang,Anja Groth

doi:10.1016/j.molcel.2021.03.041

Abstract

SummaryFrom 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.

Highlights

In its simplest form, chromatin consists of an array of repeating subunits called nucleosomes, each of which contains a complex of eight interwoven histone proteins that wrap 146 bp of DNA in a left-handed superhelix (Luger et al, 1997)
We identified DNAJC9 as a co-chaperone of MCM2 and TONSL that can substitute for ASF1
The heat shock co-chaperone DNAJC9 functions as a histone chaperone To identify potentially uncharacterized histone chaperones, we profiled the histone-dependent interactions of the histone chaperones MCM2 and TONSL by comparing the interactomes of their wild-type (WT) and histone binding mutant (HBM) forms in SILAC label swap co-immunoprecipitation experiments (Figures 1A–1C)

Summary

Introduction

In its simplest form, chromatin consists of an array of repeating subunits called nucleosomes, each of which contains a complex of eight interwoven histone proteins that wrap 146 bp of DNA in a left-handed superhelix (Luger et al, 1997). Given the high affinity of histones for both DNA and RNA, navigating the cellular landscape from synthesis on the ribosome to a specific site in the genome is a major challenge in histone supply. Throughout this process, histone chaperones shield histones from spurious interactions by binding to the exact same surfaces of histones required for nucleosome assembly (Hammond et al, 2017; Mattiroli et al, 2015; Pardal et al, 2019). Histone chaperones thereby provide pathways for histone recycling, de novo deposition, and exchange, which are central to the maintenance and plasticity of chromatin (Gurard-Levin et al, 2014; Hammond et al, 2017)

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Results

Discussion

Conclusion