DNAJC9 integrates heat shock molecular chaperones into the histone chaperone network

Abstract

Summary 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.

A J Domain Protein Functions as a Histone Chaperone to Maintain Genome Integrity and the Response to DNA Damage in a Human Fungal Pathogen

“…2b ). This is consistent with the recent findings in humans that DNAJC9 interacts with histones and the human Hsp71 ortholog, Hsc70 ( 22 ). Altogether, these results suggest a role for Dnj4 in histone chaperoning.…”

“…1a ). In support of this prediction, we found that Dnj4 was an ortholog of the human cochaperone DNAJC9 ( 22 ) and to proteins in a number of fungal species, with the exception of Saccharomyces cerevisiae . We examined the domain structure of Dnj4 and generated a maximum likelihood tree with DNAJC9 and orthologous amino acid sequences obtained from UniProt for several fungi.…”

“…With regard to domain structure, the recent characterization of DNAJC9 identified a C-terminal histone binding domain (HBD); this domain was largely conserved across species, although an insertion was observed in the alignment of some of the fungal sequences ( Fig. S1b ) ( 22 ).…”

A specific role for Importin-5 and NASP in the import and nuclear hand-off of monomeric H3

“…Looking at histone H3, we found that histone chaperones previously characterised to interact with a constitutive H3-H4 dimer (ASF1A/B, CHAF1A/B, RBBP4, DNAJC9), the H4 tail-binding HAT1 complex (HAT1, RBBP7), Imp4 and histone H4 were enriched on wild-type H3 compared to mutants, as expected (Fig. 2A) (Groth et al, 2005;Tagami et al, 2004;Smith and Stillman, 1989;Tyler et al, 1999;Kleff et al, 1995;Hammond et al, 2021). Interactors that bound indiscriminately to wild type and monomeric H3 included the histone chaperones NASP, UBR7, C1QBP, Imp5, and to a lesser extent NAP1L1/4 and members of the HSP70 family of molecular chaperones HSPA1B, HSPA6 and HSPA8 (Fig.…”

ATAD2 controls chromatin-bound HIRA turnover

“…Overall, these studies also generalize the idea of a need for ATP hydrolysis and the involvement of ATPase activity in the control of histone chaperone activity. Along these lines, a recent publication demonstrated that DNAJC9 recruits HSP70 ATPase activity into the histone supply chain ( Hammond et al, 2021 ). The authors also showed that histone-bound DNAJC9 bearing a mutation that disabled the protein from mediating ATP hydrolysis by HSP70 became trapped on chromatin.…”