Affinage

HIRA

Protein HIRA · UniProt P54198

Length
1017 aa
Mass
111.8 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HIRA is the central scaffold of a histone H3.3-specific chaperone complex that deposits H3.3 into chromatin in a DNA replication-independent manner, thereby maintaining chromatin homeostasis across replicating and non-dividing cells (PMID:12049744, PMID:23602572). Within the HIRA/UBN1/CABIN1 (HUCA) complex, the UBN1 subunit directly recognizes H3.3 through its H3.3-specific residues Ala87 and Gly90, with HIRA enhancing this binding affinity (PMID:30285846); UBN1 docks onto the HIRA N-terminal WD repeats through a tight 1:1 NHRD interaction (PMID:19029251, PMID:22401310), while HIRA itself forms a homotrimer that engages CABIN1 and is required for de novo H3.3 deposition and recruitment to UV damage sites (PMID:30082790). HIRA also binds ASF1a through its B domain in a manner mutually exclusive with CAF-1 (PMID:16980972), and these two interfaces define functionally separable activities: trimerization/UBN1-dependent de novo deposition versus ASF1-dependent recycling of pre-existing H3.3 during transcription (PMID:32895554). The complex is targeted to active promoters and enhancers genome-wide, partly through a physical interaction with RPA that licenses HIRA chromatin association and H3.3 deposition (PMID:23602572, PMID:28107649). Through replication-independent H3.3 deposition, HIRA enforces senescence-associated heterochromatin foci (SAHF) formation by entering PML nuclear bodies and cooperating with ASF1a and UBN1 (PMID:15621527, PMID:17242198, PMID:19029251), maintains active chromatin and H4K16ac to suppress oncogene-induced neoplasia (PMID:25512559), assembles paternal chromatin at fertilization by depositing H3.3 onto the decondensing sperm genome (PMID:16251970, PMID:17967064, PMID:25087892), and governs lineage-specific gene programs in neural, muscle, cardiac and hematopoietic differentiation via H3.3 deposition at developmental enhancers (PMID:30285846, PMID:34103504, PMID:27518902, PMID:25847244). HIRA additionally functions in intrinsic antiviral immunity, depositing H3.3 onto incoming viral genomes to restrict lytic infection and promoting transcription of interferon-stimulated genes (PMID:28981850, PMID:30901352). Its activity is tuned post-translationally by cyclin A/E-cdk2 phosphorylation (PMID:11238922) and OGT-mediated O-GlcNAcylation at Ser231, which promotes HIRA-H3.3 complex assembly (PMID:27217568).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1998 Medium

    Establishing HIRA's biochemical wiring, this work showed HIRA physically engages core histones and a developmental transcription factor, framing it as a histone-handling protein with regulatory connections.

    Evidence Yeast two-hybrid, GST pull-down, and co-IP with deletion mapping identifying C-terminal H2B/H4-binding regions and HIRIP3/Pax3 interactions

    PMID:9710638 PMID:9731536

    Open questions at the time
    • Did not establish histone deposition activity or H3.3 specificity
    • Pax3 interaction rested on a single yeast two-hybrid without functional follow-up
  2. 2001 High

    This work answered how HIRA is coupled to the cell cycle, identifying it as a cdk2 substrate whose activity restrains S-phase progression.

    Evidence In vitro kinase assays, RXL/phosphoacceptor mutagenesis, in vivo phosphorylation, and ectopic expression causing S-phase arrest

    PMID:11238922

    Open questions at the time
    • Functional consequence of Thr555 phosphorylation on chaperone activity not resolved
    • Link between phosphorylation and chromatin assembly not directly tested
  3. 2002 High

    This established HIRA's defining biochemical function: a chaperone driving nucleosome assembly specifically on non-replicating DNA, distinguishing it from replication-coupled pathways.

    Evidence In vitro nucleosome assembly, HIRA immunodepletion from Xenopus egg extracts, and rescue with recombinant HIRA plus histones

    PMID:12049744

    Open questions at the time
    • H3.3 specificity not yet demonstrated
    • Subunit composition of the active chaperone complex unknown
  4. 2005 High

    Two studies connected HIRA's replication-independent assembly to physiology: SAHF/senescence in somatic cells and H3.3-specific paternal chromatin assembly at fertilization.

    Evidence Co-IP of HIRA-ASF1a, PML body imaging, and dominant-negative mutants for senescence; Drosophila maternal-effect mutants with H3.3 vs H3 immunofluorescence for fertilization

    PMID:15621527 PMID:16251970

    Open questions at the time
    • Molecular basis of H3.3 selectivity not yet defined
    • How HIRA is recruited to PML bodies unresolved
  5. 2006 High

    Structural definition of the ASF1a-HIRA interface and its mutual exclusivity with CAF-1 explained how HIRA is partitioned away from replication-coupled assembly.

    Evidence X-ray crystallography of the ASF1a-HIRA B-domain heterodimer with binding assays and mutagenesis

    PMID:16980972

    Open questions at the time
    • Functional role of ASF1a in HIRA-dependent deposition versus recycling not yet distinguished
    • Did not address other HUCA subunits
  6. 2007 High

    Genetic and pathway dissection refined HIRA's roles: its sole essential Drosophila function is ASF1-independent paternal chromatin assembly, and PML-body localization is mechanistically required for SAHF.

    Evidence Drosophila Hira null allele with protamine/H3.3 immunofluorescence and ASF1 epistasis; dominant-negative HIRA and PML disruption with senescence readouts

    PMID:17242198 PMID:17967064

    Open questions at the time
    • Mechanism distinguishing ASF1-dependent from ASF1-independent HIRA activities not yet defined
    • Convergence with the pRB pathway only partially mapped
  7. 2008 High

    This identified UBN1 as a core HIRA-complex subunit binding the HIRA WD repeats and required for the SAHF-associated repressive chromatin program.

    Evidence Yeast two-hybrid, co-IP, UBN1 knockdown with SAHF readout, and ChIP at repressed proliferation genes

    PMID:19029251

    Open questions at the time
    • Direct H3.3 recognition by UBN1 not yet shown
    • Precise UBN1 interaction region within HIRA WD repeats not mapped
  8. 2010 Medium

    Resolving how H3.3 is sorted before deposition, this showed predeposition H3.3 partitions into independent HIRA and Daxx complexes, establishing parallel chaperone routes.

    Evidence Biochemical fractionation/co-IP and HIRA knockout mouse ES cells

    PMID:21047901

    Open questions at the time
    • Single-lab biochemical characterization without structural detail
    • Functional division of labor between HIRA and Daxx routes not fully defined
  9. 2011 Medium

    This revealed an ASF1a-independent HIRA role in ALT cancer cells, supporting APB and HP1 organization at PML bodies.

    Evidence HIRA versus ASF1a knockdown with APB/HP1 immunofluorescence and colocalization

    PMID:21347226

    Open questions at the time
    • Mechanism by which HIRA promotes APB formation not defined
    • Single-lab loss-of-function without reconstitution
  10. 2012 High

    Quantitative mapping defined the minimal UBN1 NHRD-HIRA WD nanomolar interface required for HUCA stability, and a separate study linked HIRA-dependent H3.3 deposition to transcriptional reprogramming.

    Evidence Analytical ultracentrifugation/SPR with mutagenesis for the NHRD interface; nuclear transfer to Xenopus oocytes with HIRA knockdown for reprogramming

    PMID:22401310 PMID:23102146

    Open questions at the time
    • How NHRD binding controls H3.3 handoff not resolved
    • Reprogramming study limited to oocyte transfer system
  11. 2013 High

    Genome-wide mapping placed the HIRA complex at active promoters and enhancers and demonstrated it is required for H3.3 deposition at those sites.

    Evidence ChIP-seq of HIRA/UBN1/ASF1a/H3.3, co-IP, and knockdown with deposition readout

    PMID:23602572

    Open questions at the time
    • Recruitment mechanism to specific loci not yet identified
    • Functional consequences for transcription not fully resolved
  12. 2014 High

    Three studies extended HIRA's H3.3 deposition to in vivo physiology: tumor suppression via maintenance of active chromatin in senescent cells and essential zygotic functions including replication and rRNA transcription.

    Evidence ChIP-seq, HIRA KO and in vivo tumor models; conditional maternal Hira knockout with EdU and rRNA transcription assays

    PMID:25087892 PMID:25512559

    Open questions at the time
    • Mechanistic link between H3.3 deposition and H4K16ac retention not fully defined
    • How zygotic H3.3 deposition enables replication and rRNA transcription not mechanistically resolved
  13. 2015 High

    Studies established HIRA's requirement for continuous H3.3 deposition in non-replicating oocytes to protect chromatin and methylation states, and its direct cooperation with RUNX1 in hematopoietic gene activation.

    Evidence Conditional oocyte Hira KO with DNase sensitivity, γH2AX, RNA-seq and bisulfite sequencing; co-IP of HIRA-RUNX1 with ChIP at the Runx1 +24 enhancer

    PMID:25847244 PMID:26549683

    Open questions at the time
    • How H3.3 loss leads to DNA damage and methylation defects not mechanistically resolved
    • RUNX1 interaction single-lab without structural detail
  14. 2016 Medium

    This year added post-translational and partner-level regulation: OGT O-GlcNAcylates HIRA at Ser231 to promote HIRA-H3.3 assembly, while PHB stabilizes HIRA and links it to metabolism, and conditional KO defined an in vivo cardiac developmental role.

    Evidence Co-IP, MS site mapping and S231A mutagenesis with assembly/senescence assays; PHB co-IP with ChIP-seq and metabolite analysis; cardiac conditional Hira KO with ChIP at the TTe enhancer

    PMID:27217568 PMID:27518902 PMID:27939217

    Open questions at the time
    • Each mechanism rests on single-lab evidence
    • How Ser231 O-GlcNAcylation structurally promotes complex formation not defined
  15. 2017 High

    Studies defined HIRA's targeting cofactor RPA and established its role in intrinsic antiviral immunity, while neural studies linked HIRA to differentiation timing.

    Evidence shRNA screen, co-IP and ChIP-seq for RPA-HIRA; HIRA KO with viral replication assays and in vivo CMV; HIRA-Setd1A co-IP with H3K4me3 ChIP in neural progenitors

    PMID:28107649 PMID:28515277 PMID:28981850

    Open questions at the time
    • How RPA selects HIRA target loci not resolved
    • Whether viral DNA H3.3 deposition uses the canonical HUCA mechanism not fully defined
  16. 2018 High

    Structural and biochemical dissection defined the H3.3-recognition determinant (UBN1 binding Ala87/Gly90) and the HIRA homotrimer-CABIN1 architecture required for de novo deposition.

    Evidence Crystallography of the HIRA trimerization domain, AUC, KO rescue and UV recruitment; H3.3 residue mutagenesis with ChIP-seq and neural differentiation assays

    PMID:30082790 PMID:30285846

    Open questions at the time
    • How trimerization couples to UBN1-mediated H3.3 recognition mechanistically not resolved
    • Structure of the assembled holo-complex on a nucleosome not determined
  17. 2020 High

    This resolved that HIRA executes two mechanistically separable activities — de novo deposition (trimerization/UBN1-dependent) and old H3.3 recycling (ASF1-dependent) — during transcription.

    Evidence SNAP-tag pulse-chase distinguishing new and old histones with trimerization, UBN1, and ASF1-interaction mutants plus ChIP-seq

    PMID:32895554

    Open questions at the time
    • How the choice between deposition and recycling is regulated in vivo unknown
    • Single-lab study
  18. 2021 High

    Conditional muscle KO showed HIRA-dependent H3.3 deposition safeguards lineage identity by preventing aberrant H3K4me3 and ectopic gene expression at silent promoters.

    Evidence Conditional Hira KO in myogenic cells with ChIP-seq for H3.3/H3K27ac/H3K4me3, RNA-seq, and in vivo regeneration assays

    PMID:34103504

    Open questions at the time
    • Mechanism by which H3.3 loss permits MLL1/MLL2 recruitment not defined
    • Generality across other stem cell lineages not tested
  19. 2022 Medium

    This connected HIRA to H2A.Z chromatin by showing the HIRA complex partners with SRCAP to co-deposit H3.3 and H2A.Z and preset transcriptional poising.

    Evidence In vitro and in vivo co-IP of HIRA-SRCAP, CUT&Tag for H3.3/H2A.Z, and HIRA-component knockdowns in mESCs

    PMID:34893908

    Open questions at the time
    • Whether co-deposition is coupled or sequential not resolved
    • Single-lab study
  20. 2023 Medium

    This defined the SUMO-SIM mechanism of HIRA recruitment to PML bodies and clarified that PML acts as a nuclear depot regulating HIRA distribution rather than being strictly required for ISG H3.3 deposition.

    Evidence SUMO-SIM interaction assays, PML/SP100/DAXX manipulation, HIRA imaging, and ChIP for H3.3 at ISGs with RNA-seq

    PMID:37227756

    Open questions at the time
    • How SUMO-SIM recruitment is signal-regulated not fully resolved
    • Functional purpose of PML sequestration of HIRA unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HIRA's locus-specific recruitment, post-translational state, and choice between de novo deposition versus recycling are integrated and signal-regulated in vivo remains open.
  • No structure of the holo-HUCA complex engaging a nucleosome
  • Regulatory logic coordinating RPA, PML, phosphorylation and O-GlcNAcylation not unified
  • How locus-specific targeting selects among thousands of active promoters/enhancers unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 5 GO:0060090 molecular adaptor activity 4 GO:0003677 DNA binding 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1474165 Reproduction 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3
Partners
ASF1ACABIN1OGTRPA1RUNX1SRCAPUBN1
Complex memberships
HIRA-ASF1a complexHIRA/UBN1/CABIN1 (HUCA) complexRPA-HIRA-H3.3 complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 HIRA is required for a DNA replication-independent nucleosome assembly pathway. Xenopus HIRA bound purified core histones and promoted their deposition onto plasmid DNA in vitro. Immunodepletion of HIRA from Xenopus egg extracts severely impaired nucleosome assembly on non-replicated DNA but not on replicating DNA, and this defect was rescued by reintroduction of HIRA with (H3-H4)2 tetramers. In vitro nucleosome assembly assay; HIRA immunodepletion from Xenopus egg extracts; rescue reconstitution with recombinant HIRA and histones Molecular cell High 12049744
2005 HIRA drives formation of macroH2A-containing senescence-associated heterochromatin foci (SAHF) and senescence-associated cell cycle exit. As cells approach senescence, HIRA enters PML nuclear bodies, where it transiently colocalizes with HP1 proteins prior to HP1 incorporation into SAHF. A physical complex containing HIRA and ASF1a is rate-limiting for SAHF formation and onset of senescence. Co-immunoprecipitation of HIRA-ASF1a complex; immunofluorescence/live-cell imaging of HIRA localization to PML bodies; dominant-negative HIRA mutants; ASF1a knockdown with SAHF/senescence phenotypic readout Developmental cell High 15621527
2005 HIRA (Drosophila Hira/sésame) is essential for replication-independent nucleosome assembly during sperm nucleus decondensation at fertilization, specifically mediating incorporation of histone H3.3 (not H3) into paternal chromatin before the first round of DNA replication. Drosophila maternal-effect point mutant (ssm/Hira); chromatin immunofluorescence for H3.3 vs H3 in paternal pronucleus; phenotypic analysis of male pronucleus formation failure Nature High 16251970
2006 Crystal structure of the ASF1a-HIRA heterodimer revealed that the HIRA B domain forms an antiparallel beta-hairpin that binds perpendicular to the beta-sandwich of ASF1a via beta-sheet, salt bridge and van der Waals contacts. The N- and C-terminal regions of ASF1a and ASF1b determine differential affinities for HIRA. CAF-1 p60 uses B domain-like motifs to competitively bind ASF1a, precluding simultaneous HIRA binding. X-ray crystallography of ASF1a-HIRA complex; biochemical binding assays; mutagenesis Nature structural & molecular biology High 16980972
2007 In Drosophila, the only essential function of HIRA is assembly of paternal chromatin during male pronucleus formation. HIRA-dependent H3.3 nucleosome assembly on paternal DNA does not require ASF1. Protamine removal from sperm chromatin is unaffected in Hira mutants, demonstrating that protamine removal and histone deposition are functionally distinct processes. Hira null allele by homologous recombination; phenotypic analysis; immunofluorescence for H3.3 and protamines; genetic epistasis with ASF1 PLoS genetics High 17967064
2007 HIRA localization to PML nuclear bodies is required for SAHF formation. Dominant-negative HIRA mutants that block HIRA's localization to PML bodies prevent SAHF formation, as does a PML-RARα fusion protein that disrupts PML bodies. HIRA translocation to PML bodies occurs independently of functional pRB and p53, but downstream HIRA/ASF1a pathway cooperates in parallel with pRB to form SAHF, with convergence occurring through DNAJ-domain protein DNAJA2. Dominant-negative HIRA mutants; PML-RARα disruption of PML bodies; immunofluorescence; epistasis analysis with pRB/p53 pathway mutants; co-IP with DNAJA2 Molecular and cellular biology High 17242198
2008 UBN1 (human ortholog of yeast Hpc2p) directly interacts with the N-terminal WD repeats of HIRA via its Hpc2-related domain (HRD), and is indispensable for SAHF formation. UBN1 binds proliferation-promoting genes repressed by SAHF and associates with H3K9 histone methyltransferase activity. Yeast two-hybrid; co-immunoprecipitation; UBN1 knockdown with SAHF phenotypic readout; chromatin immunoprecipitation Molecular and cellular biology High 19029251
2001 Human HIRA is an in vivo substrate of cyclin A- and E-cdk2 kinases. HIRA bound to and was phosphorylated by cyclin A- and E-cdk2 in vitro in an RXL-dependent manner. HIRA was phosphorylated in vivo on two consensus cdk2 sites including Thr555 (phosphorylated in S phase), and this phosphorylation was blocked by p21(cip1). Ectopic HIRA expression caused S-phase arrest. In vitro kinase assay; site-directed mutagenesis of RXL and phosphoacceptor sites; in vivo phosphorylation analysis; p21 inhibition; ectopic expression with cell cycle phenotype readout Molecular and cellular biology High 11238922
1998 HIRA directly interacts with core histones H2B and H4 (mapped to the carboxy-terminal region of HIRA) and with transcription factor Pax3. H2B- and H4-binding domains were overlapping but distinguishable in HIRA's C-terminus; the H2B interaction region was mapped to the amino-terminal tail of H2B and the second alpha helix of H4. HIRA also interacts with a novel protein HIRIP3, which itself binds histones H2B and H3. Yeast two-hybrid; GST pull-down; co-immunoprecipitation from cellular extracts; deletion mapping Molecular and cellular biology Medium 9710638
1998 HIRA interacts with the transcription factor Pax3 (a homeodomain protein whose haploinsufficiency causes Waardenburg syndrome/DiGeorge phenocopy). This interaction was identified by yeast two-hybrid and places HIRA in a potential developmental regulatory complex. Yeast two-hybrid interaction screen Nature genetics Low 9731536
2013 The HIRA complex (HIRA, UBN1, CABIN1) colocalizes with ASF1a and H3.3 primarily at active promoters and active/poised enhancers genome-wide. HIRA is required for deposition of H3.3 at its binding sites. Physical interactions between the HIRA complex and transcription factors, a chromatin insulator, and an ATP-dependent chromatin-remodeling complex were identified. ChIP-seq for HIRA, UBN1, ASF1a, H3.3; co-immunoprecipitation for protein-protein interactions; knockdown with H3.3 deposition phenotype readout Cell reports High 23602572
2014 HIRA deposits histone H3.3 and H4 into chromatin of non-replicating senescent cells. HIRA colocalizes with H3.3 at promoters of expressed genes. HIRA is required for retention of H4K16ac at active gene promoters in senescent cells and in vivo, and is required for suppression of oncogene-induced neoplasia. Canonical histones in senescent cells are expressed via alternative mRNA splicing. ChIP-seq; HIRA knockdown/knockout; H3.3/H4 deposition assays; in vivo mouse tumor suppression experiments; RNA-seq Genes & development High 25512559
2014 Maternal Hira (histone chaperone) is required for male pronucleus formation in the mouse zygote by enabling nucleosome assembly in the sperm genome. Hira-mediated H3.3 incorporation is also required for DNA replication and ribosomal RNA transcription in the zygote; Hira/H3.3-dependent rRNA transcription is required for first cleavage. Conditional maternal knockout of Hira; immunofluorescence for H3.3; DNA replication assays (EdU incorporation); rRNA transcription analysis; parthenogenetic activation assays Developmental cell High 25087892
2015 Hira is required for continuous replication-independent H3.3/H4 deposition in non-replicating mouse oocytes. Deletion of Hira in developing oocytes increases DNase I sensitivity of chromatin, causes accumulation of DNA damage, reduces the dynamic range of gene expression, produces spurious transcripts, and impairs de novo DNA methylation. Conditional Hira knockout in oocytes; ATAC/DNase I sensitivity; DNA damage markers (γH2AX); RNA-seq; bisulfite sequencing for DNA methylation Molecular cell High 26549683
2017 Replication protein A (RPA) physically interacts with HIRA to form RPA-HIRA-H3.3 complexes. RPA co-localizes with HIRA and H3.3 at gene promoters and enhancers. Depletion of RPA1 dramatically reduces HIRA association with chromatin and deposition of newly synthesized H3.3 at promoters and enhancers, altering transcription. shRNA screen; co-immunoprecipitation; ChIP-seq; pulse-chase H3.3 deposition assay; RPA1 knockdown with HIRA chromatin association and H3.3 deposition readouts Molecular cell High 28107649
2018 HIRA forms a stable homotrimer that binds two subunits of CABIN1. A HIRA trimerization-defective mutant interacts less efficiently with CABIN1, fails to enrich at DNA damage sites upon UV irradiation, and cannot rescue new H3.3 deposition in HIRA knockout cells. Structural homology with homotrimeric Ctf4/AND-1 was identified. Biochemical analysis; X-ray crystallography of HIRA trimerization domain; analytical ultracentrifugation; HIRA knockout cell rescue assays; UV damage recruitment assay Nature communications High 30082790
2018 UBN1 (and UBN2) subunits of the HIRA complex are primarily responsible for specific recognition and direct binding of H3.3. The HIRA subunit enhances UBN1 binding affinity for H3.3. Both Ala87 and Gly90 residues of H3.3 are required and sufficient for specific recognition by UBN1. Disruption of UBN1/UBN2 histone chaperone activity (FID/AAA mutation) impairs H3.3 deposition at developmental gene promoters and causes failure of neural differentiation. Biochemical binding assays; mutagenesis of H3.3 residues; ChIP-seq; neural differentiation assays with FID/AAA mutants BMC biology High 30285846
2010 Before deposition, H3.3 exists in two biochemically distinct predeposition complexes: one associated with HIRA/UBN1/CABIN1, and one associated with Daxx. Deletion of HIRA impairs HIRA complex integrity but does not abolish Daxx association with H3.3/H4, demonstrating these are independent parallel chaperone systems. Biochemical fractionation/co-IP; HIRA knockout mouse ES cells; protein complex characterization Cold Spring Harbor symposia on quantitative biology Medium 21047901
2012 HIRA-dependent H3.3 deposition at rDNA, major satellite repeats, and Oct4 regulatory regions is required for transcriptional reprogramming following nuclear transfer to Xenopus oocytes. This major H3.3 deposition occurs in the absence of DNA replication and is HIRA-dependent and transcription-dependent. Nuclear transfer to Xenopus oocytes; HIRA knockdown; ChIP for oocyte-derived H3.3; transcriptional reprogramming assays Epigenetics & chromatin Medium 23102146
2017 HIRA deposits histone H3.3 onto incoming viral (HSV, CMV) and plasmid DNAs in the nucleus. Following viral infection or DNA transfection, HIRA re-localizes to PML bodies and co-localizes with viral genomes. HIRA is required for suppression of viral gene expression and lytic infection; it restricts murine CMV replication in vivo. Immunofluorescence; ChIP for HIRA on viral DNA; HIRA knockout/knockdown with viral replication assays; in vivo CMV infection model Nucleic acids research High 28981850
2019 HIRA localizes to PML nuclear bodies (in a JAK-, CDK-, and Sp100-dependent manner) following innate immune signaling activation during HSV-1 infection, and promotes transcriptional upregulation of innate immune genes including ISGs, MHC-I antigen presentation, and cytokine signaling genes. PML is required for HIRA enrichment onto ISGs. HIRA's anti-viral functions are antagonized by HSV-1 ICP0 ubiquitin ligase. Immunofluorescence; RNA-seq; ChIP-seq; HIRA knockdown; kinase inhibitor experiments; ICP0 overexpression PLoS pathogens Medium 30901352
2020 HIRA mediates two distinct pathways for H3.3 handling during transcription: (1) de novo H3.3 deposition requiring HIRA trimerization and UBN1; (2) recycling of old H3.3 requiring ASF1-HIRA interaction but independent of UBN1 or HIRA trimerization. These were distinguished using SNAP-tag pulse-chase to separate new and old histones. SNAP-tag pulse-chase labeling; HIRA trimerization mutants; UBN1 knockdown; ASF1-HIRA interaction mutants; ChIP-seq Nature structural & molecular biology High 32895554
2016 O-GlcNAc transferase (OGT) interacts with UBN1 and O-GlcNAcylates HIRA at Ser231. This modification promotes formation of the HIRA-H3.3 complex and H3.3 nucleosome assembly. The HIRA S231A O-GlcNAcylation-deficient mutant compromises HIRA-H3.3 complex formation and H3.3 nucleosome assembly, and delays premature cellular senescence. Co-immunoprecipitation; mass spectrometry identification of O-GlcNAcylation site; HIRA S231A mutagenesis; H3.3 nucleosome assembly assay; senescence assays Proceedings of the National Academy of Sciences of the United States of America Medium 27217568
2012 A smaller conserved region within UBN1 (residues 41-77, termed NHRD) is essential for interaction with HIRA WD repeats; the previously described HRD (residues 120-175) is dispensable for this interaction. NHRD and HIRA WD repeats form a tight 1:1 complex (nanomolar Kd). Mutagenesis identified key NHRD residues required for HIRA interaction, HUCA complex stability in vitro and in vivo, and chromatin organization in primary human cells. Analytical ultracentrifugation; surface plasmon resonance/binding affinity measurement; mutagenesis; co-IP; chromatin organization assays Biochemistry High 22401310
2016 Prohibitin (PHB) forms protein complexes with HIRA, stabilizes HIRA complex component protein levels, and together with HIRA controls global H3.3 deposition and gene expression in human ESCs. PHB and HIRA regulate chromatin architecture at promoters of isocitrate dehydrogenase genes to promote α-ketoglutarate production, linking epigenetic organization to metabolic regulation. Co-immunoprecipitation; siRNA knockdown; ChIP-seq; metabolite analysis; hESC self-renewal assays Cell stem cell Medium 27939217
2017 HIRA knockdown in neural progenitor cells reduces proliferation, increases terminal mitosis and cell cycle exit, and causes premature neuronal differentiation. HIRA enhances β-catenin expression by recruiting H3K4 trimethyltransferase Setd1A, increasing H3K4me3 levels at the β-catenin promoter. Overexpression of HIRA or its N-terminal domain rescues neurogenesis defects. HIRA knockdown; co-immunoprecipitation (HIRA-Setd1A); ChIP for H3K4me3; rescue overexpression; neural progenitor proliferation/differentiation assays The Journal of cell biology Medium 28515277
2021 Conditional ablation of HIRA in myogenic cells leads to transcriptional changes consistent with loss of skeletal muscle lineage identity, compromises muscle stem cell regeneration and self-renewal. Hira-deficient cells show reduced H3.3 deposition and H3K27ac at muscle gene regulatory regions, and ectopic expression of alternative lineage genes via MLL1/MLL2-mediated increase of H3K4me3 at silent promoters. Conditional Hira knockout in muscle; ChIP-seq for H3.3, H3K27ac, H3K4me3; RNA-seq; muscle regeneration assays in vivo Nature communications High 34103504
2016 Conditional ablation of Hira in cardiogenic mesoderm causes ventricular and atrial septal defects and embryonic lethality. HIRA directly regulates Tnni2 and Tnnt3 expression by binding a GAGA-rich enhancer (TTe) bound by NKX2.5, with HIRA-dependent H3.3 enrichment at this enhancer in ESC-derived cardiomyocytes. Conditional Hira knockout in heart; ChIP for HIRA and H3.3 at TTe enhancer; gene expression analysis; in vitro ESC differentiation to cardiomyocytes PloS one Medium 27518902
2015 HIRA directly interacts with RUNX1 transcription factor and promotes RUNX1-mediated activation of hematopoietic stem cell target genes. HIRA-mediated incorporation of H3.3 at the Runx1 +24 intronic enhancer is essential for Runx1 expression during endothelial-to-hematopoietic transition. Co-immunoprecipitation of HIRA-RUNX1; HIRA knockdown; ChIP for H3.3 at Runx1 +24 enhancer; ESC differentiation assays The Journal of biological chemistry Medium 25847244
2022 HIRA complex interacts with SRCAP complex (an H2A.Z chaperone) through the HIRA subunit. Depletion of HIRA complex components results in significant decreases of H2A.Z enrichment genome-wide. HIRA complex and SRCAP cooperatively deposit H3.3 and H2A.Z at active promoters and enhancers to preset transcriptional potential (poised state) in mESCs. Co-immunoprecipitation of HIRA-SRCAP in vivo and in vitro; CUT&Tag for H3.3 and H2A.Z; HIRA component knockdowns; chromatin accessibility assays Nucleic acids research Medium 34893908
2023 HIRA is recruited to PML nuclear bodies via intermolecular SUMO-SIM interactions. PML nuclear bodies act as nuclear depot centers regulating HIRA distribution in the nucleus, dependent on SP100 and DAXX/H3.3 levels. Upon IFN-I stimulation, HIRA and PML cooperate for prolonged H3.3 deposition at transcriptional end sites of ISGs; however, HIRA accumulation in PML NBs is dispensable for H3.3 deposition on ISGs. SUMO-SIM interaction assays; PML/SP100/DAXX manipulation; HIRA localization imaging; ChIP for H3.3 at ISGs; RNA-seq eLife Medium 37227756
2011 HIRA is required for HP1-mediated formation of ALT-associated PML nuclear bodies (APBs) in ALT cancer cells, independently of ASF1a. Knockdown of HIRA (but not ASF1a) significantly reduced large APB formation and HP1 localization to PML bodies, demonstrating a unique ASF1a-independent role for HIRA. HIRA and ASF1a knockdown; immunofluorescence for APBs and HP1; colocalization analysis PloS one Medium 21347226

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Ssn6-Tup1 is a general repressor of transcription in yeast. Cell 603 1739976
2005 Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Developmental cell 556 15621527
2002 HIRA is critical for a nucleosome assembly pathway independent of DNA synthesis. Molecular cell 337 12049744
1995 Repression by SSN6-TUP1 is directed by MIG1, a repressor/activator protein. Proceedings of the National Academy of Sciences of the United States of America 336 7724528
1994 Functional dissection of the yeast Cyc8-Tup1 transcriptional co-repressor complex. Nature 302 8008070
2002 Hog1 kinase converts the Sko1-Cyc8-Tup1 repressor complex into an activator that recruits SAGA and SWI/SNF in response to osmotic stress. Molecular cell 291 12086627
2005 The histone H3.3 chaperone HIRA is essential for chromatin assembly in the male pronucleus. Nature 280 16251970
2000 Turning genes off by Ssn6-Tup1: a conserved system of transcriptional repression in eukaryotes. Trends in biochemical sciences 266 10871883
2000 Identification and characterization of TUP1-regulated genes in Candida albicans. Genetics 266 10978273
2000 TUP1, CPH1 and EFG1 make independent contributions to filamentation in candida albicans. Genetics 222 10790384
1994 The WD repeats of Tup1 interact with the homeo domain protein alpha 2. Genes & development 197 7995523
2001 TUP1 utilizes histone H3/H2B-specific HDA1 deacetylase to repress gene activity in yeast. Molecular cell 190 11172717
1991 The CYC8 and TUP1 proteins involved in glucose repression in Saccharomyces cerevisiae are associated in a protein complex. Molecular and cellular biology 189 2038333
1990 Characterization of TUP1, a mediator of glucose repression in Saccharomyces cerevisiae. Molecular and cellular biology 185 2247069
1994 The global transcriptional regulators, SSN6 and TUP1, play distinct roles in the establishment of a repressive chromatin structure. Genes & development 168 7926740
2006 Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly. Nature structural & molecular biology 158 16980972
1999 HWP1 functions in the morphological development of Candida albicans downstream of EFG1, TUP1, and RBF1. Journal of bacteriology 148 10464197
2014 Hira-mediated H3.3 incorporation is required for DNA replication and ribosomal RNA transcription in the mouse zygote. Developmental cell 141 25087892
2000 Ssn6-Tup1 interacts with class I histone deacetylases required for repression. Genes & development 137 11069890
2007 Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci. Molecular and cellular biology 128 17242198
2014 HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes & development 124 25512559
2013 Placing the HIRA histone chaperone complex in the chromatin landscape. Cell reports 119 23602572
2006 Transcriptional repression by Tup1-Ssn6. Biochemistry and cell biology = Biochimie et biologie cellulaire 118 16936817
1998 HIRA, a mammalian homologue of Saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax3. Nature genetics 117 9731536
1998 Functional relationships of Srb10-Srb11 kinase, carboxy-terminal domain kinase CTDK-I, and transcriptional corepressor Ssn6-Tup1. Molecular and cellular biology 115 9488431
1996 The Cyc8 (Ssn6)-Tup1 corepressor complex is composed of one Cyc8 and four Tup1 subunits. Molecular and cellular biology 115 8943325
2008 Groucho/Tup1 family co-repressors in plant development. Trends in plant science 113 18314376
2011 The Cyc8-Tup1 complex inhibits transcription primarily by masking the activation domain of the recruiting protein. Genes & development 111 22156212
2002 Cti6, a PHD domain protein, bridges the Cyc8-Tup1 corepressor and the SAGA coactivator to overcome repression at GAL1. Molecular cell 110 12086626
2000 Structure of the C-terminal domain of Tup1, a corepressor of transcription in yeast. The EMBO journal 106 10856245
2008 Human UBN1 is an ortholog of yeast Hpc2p and has an essential role in the HIRA/ASF1a chromatin-remodeling pathway in senescent cells. Molecular and cellular biology 104 19029251
2007 The essential role of Drosophila HIRA for de novo assembly of paternal chromatin at fertilization. PLoS genetics 104 17967064
2015 Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis. Molecular cell 103 26549683
2001 HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression. Molecular and cellular biology 102 11238922
2004 The Snf1 kinase controls glucose repression in yeast by modulating interactions between the Mig1 repressor and the Cyc8-Tup1 co-repressor. EMBO reports 100 15031717
2008 Candida albicans Tup1 is involved in farnesol-mediated inhibition of filamentous-growth induction. Eukaryotic cell 92 18424510
2005 Global roles of Ssn6 in Tup1- and Nrg1-dependent gene regulation in the fungal pathogen, Candida albicans. Molecular biology of the cell 92 15814841
1997 A complex composed of tup1 and ssn6 represses transcription in vitro. The Journal of biological chemistry 90 9111019
2001 Sfl1 functions via the co-repressor Ssn6-Tup1 and the cAMP-dependent protein kinase Tpk2. Journal of molecular biology 88 11399075
2000 Hrs1/Med3 is a Cyc8-Tup1 corepressor target in the RNA polymerase II holoenzyme. The Journal of biological chemistry 87 10722672
1998 Core histones and HIRIP3, a novel histone-binding protein, directly interact with WD repeat protein HIRA. Molecular and cellular biology 87 9710638
2012 HIRA dependent H3.3 deposition is required for transcriptional reprogramming following nuclear transfer to Xenopus oocytes. Epigenetics & chromatin 82 23102146
2001 Antagonistic remodelling by Swi-Snf and Tup1-Ssn6 of an extensive chromatin region forms the background for FLO1 gene regulation. The EMBO journal 81 11566885
2017 RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells. Molecular cell 77 28107649
1999 The Tup1-Cyc8 protein complex can shift from a transcriptional co-repressor to a transcriptional co-activator. The Journal of biological chemistry 77 9867831
1991 AAR1/TUP1 protein, with a structure similar to that of the beta subunit of G proteins, is required for a1-alpha 2 and alpha 2 repression in cell type control of Saccharomyces cerevisiae. Molecular and cellular biology 77 1904546
2004 Redundant mechanisms are used by Ssn6-Tup1 in repressing chromosomal gene transcription in Saccharomyces cerevisiae. The Journal of biological chemistry 68 15254041
2002 Histone-dependent association of Tup1-Ssn6 with repressed genes in vivo. Molecular and cellular biology 68 11784848
2011 The stress response factors Yap6, Cin5, Phd1, and Skn7 direct targeting of the conserved co-repressor Tup1-Ssn6 in S. cerevisiae. PloS one 67 21552514
1996 Characterization of rco-1 of Neurospora crassa, a pleiotropic gene affecting growth and development that encodes a homolog of Tup1 of Saccharomyces cerevisiae. Molecular and cellular biology 67 8887652
2004 The Schizosaccharomyces pombe HIRA-like protein Hip1 is required for the periodic expression of histone genes and contributes to the function of complex centromeres. Molecular and cellular biology 65 15121850
2004 Ssn6-Tup1 requires the ISW2 complex to position nucleosomes in Saccharomyces cerevisiae. The EMBO journal 64 15116071
2004 Promoter-dependent roles for the Srb10 cyclin-dependent kinase and the Hda1 deacetylase in Tup1-mediated repression in Saccharomyces cerevisiae. Molecular biology of the cell 61 15240822
2001 Ssn6-Tup1 regulates RNR3 by positioning nucleosomes and affecting the chromatin structure at the upstream repression sequence. The Journal of biological chemistry 61 11448965
2010 HIRA and Daxx constitute two independent histone H3.3-containing predeposition complexes. Cold Spring Harbor symposia on quantitative biology 60 21047901
2017 Histone chaperone HIRA deposits histone H3.3 onto foreign viral DNA and contributes to anti-viral intrinsic immunity. Nucleic acids research 59 28981850
2020 Two HIRA-dependent pathways mediate H3.3 de novo deposition and recycling during transcription. Nature structural & molecular biology 57 32895554
2003 Recruitment of Tup1-Ssn6 by yeast hypoxic genes and chromatin-independent exclusion of TATA binding protein. Eukaryotic cell 55 14665463
2009 The fission yeast HIRA histone chaperone is required for promoter silencing and the suppression of cryptic antisense transcripts. Molecular and cellular biology 54 19620282
2019 The histone chaperone HIRA promotes the induction of host innate immune defences in response to HSV-1 infection. PLoS pathogens 50 30901352
2018 Functional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit. Nature communications 50 30082790
2011 Phosphoinositide [PI(3,5)P2] lipid-dependent regulation of the general transcriptional regulator Tup1. Genes & development 50 21536737
2000 Genetic analysis of the role of Pol II holoenzyme components in repression by the Cyc8-Tup1 corepressor in yeast. Genetics 49 10924455
1997 Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome. Human molecular genetics 49 9063744
2018 HJURP antagonizes CENP-A mislocalization driven by the H3.3 chaperones HIRA and DAXX. PloS one 45 30365520
2006 Hip3 interacts with the HIRA proteins Hip1 and Slm9 and is required for transcriptional silencing and accurate chromosome segregation. The Journal of biological chemistry 44 16428807
2017 Histone chaperone HIRA regulates neural progenitor cell proliferation and neurogenesis via β-catenin. The Journal of cell biology 43 28515277
1997 An Ssn6-Tup1-dependent negative regulatory element controls sporulation-specific expression of DIT1 and DIT2 in Saccharomyces cerevisiae. Molecular and cellular biology 43 8972192
2003 Fission yeast Tup1-like repressors repress chromatin remodeling at the fbp1+ promoter and the ade6-M26 recombination hotspot. Genetics 41 14573465
2018 UBN1/2 of HIRA complex is responsible for recognition and deposition of H3.3 at cis-regulatory elements of genes in mouse ES cells. BMC biology 40 30285846
1994 Evidence that TUP1/SSN6 has a positive effect on the activity of the yeast activator HAP1. Genetics 39 8005436
2016 A Molecular Prospective for HIRA Complex Assembly and H3.3-Specific Histone Chaperone Function. Journal of molecular biology 38 27871933
2016 PHB Associates with the HIRA Complex to Control an Epigenetic-Metabolic Circuit in Human ESCs. Cell stem cell 38 27939217
2014 The yeast Cyc8-Tup1 complex cooperates with Hda1p and Rpd3p histone deacetylases to robustly repress transcription of the subtelomeric FLO1 gene. Biochimica et biophysica acta 38 25106892
2002 Role of fission yeast Tup1-like repressors and Prr1 transcription factor in response to salt stress. Molecular biology of the cell 38 12221110
1998 Mutational analysis of the Tup1 general repressor of yeast. Genetics 38 9504912
2011 Tup1 stabilizes promoter nucleosome positioning and occupancy at transcriptionally plastic genes. Nucleic acids research 37 21785133
2016 O-linked N-acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence. Proceedings of the National Academy of Sciences of the United States of America 35 27217568
2009 Regulatory diversity of TUP1 in Cryptococcus neoformans. Eukaryotic cell 35 19820119
2000 Characterization of the N-terminal domain of the yeast transcriptional repressor Tup1. Proposal for an association model of the repressor complex Tup1 x Ssn6. The Journal of biological chemistry 35 10722750
2020 Histone Loaders CAF1 and HIRA Restrict Epstein-Barr Virus B-Cell Lytic Reactivation. mBio 33 33109754
1998 Isolation and characterization of a new gene encoding a member of the HIRA family of proteins from Drosophila melanogaster. Gene 33 9611274
2012 Identification of an ubinuclein 1 region required for stability and function of the human HIRA/UBN1/CABIN1/ASF1a histone H3.3 chaperone complex. Biochemistry 32 22401310
2013 Mth1 regulates the interaction between the Rgt1 repressor and the Ssn6-Tup1 corepressor complex by modulating PKA-dependent phosphorylation of Rgt1. Molecular biology of the cell 31 23468525
2022 HIRA complex presets transcriptional potential through coordinating depositions of the histone variants H3.3 and H2A.Z on the poised genes in mESCs. Nucleic acids research 30 34893908
2020 Ahr1 and Tup1 Contribute to the Transcriptional Control of Virulence-Associated Genes in Candida albicans. mBio 30 32345638
2011 The general transcriptional repressor Tup1 is required for dimorphism and virulence in a fungal plant pathogen. PLoS pathogens 30 21909277
2012 Stabilization of the promoter nucleosomes in nucleosome-free regions by the yeast Cyc8-Tup1 corepressor. Genome research 29 23124522
2024 HIRA vs. DAXX: the two axes shaping the histone H3.3 landscape. Experimental & molecular medicine 28 38297159
2021 HIRA stabilizes skeletal muscle lineage identity. Nature communications 27 34103504
2016 HIRA Is Required for Heart Development and Directly Regulates Tnni2 and Tnnt3. PloS one 27 27518902
2014 Effects of MIG1, TUP1 and SSN6 deletion on maltose metabolism and leavening ability of baker's yeast in lean dough. Microbial cell factories 27 24993311
2008 Roles of the Aspergillus nidulans homologues of Tup1 and Ssn6 in chromatin structure and cell viability. FEMS microbiology letters 27 19054105
2018 Wor1 establishes opaque cell fate through inhibition of the general co-repressor Tup1 in Candida albicans. PLoS genetics 26 29337983
2015 Histone Chaperone HIRA in Regulation of Transcription Factor RUNX1. The Journal of biological chemistry 26 25847244
2011 HP1-mediated formation of alternative lengthening of telomeres-associated PML bodies requires HIRA but not ASF1a. PloS one 26 21347226
1998 The Tup1-Ssn6 general repressor is involved in repression of IME1 encoding a transcriptional activator of meiosis in Saccharomyces cerevisiae. Current genetics 26 9560430
2023 Interplay between PML NBs and HIRA for H3.3 dynamics following type I interferon stimulus. eLife 25 37227756
1996 Structural Organization of the WD repeat protein-encoding gene HIRA in the DiGeorge syndrome critical region of human chromosome 22. Genome research 25 8681138
2004 Altered replication timing of the HIRA/Tuple1 locus in the DiGeorge and Velocardiofacial syndromes. Gene 24 15177686

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