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Title: Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX

Abstract

The ATRX–DAXX histone chaperone complex incorporates the histone variant H3.3 at heterochromatic regions in a replication-independent manner. Here, we present a high-resolution x-ray crystal structure of an interaction surface between ATRX and DAXX. We use single amino acid substitutions in DAXX that abrogate formation of the complex to explore ATRX-dependent and ATRX-independent functions of DAXX. We find that the repression of specific murine endogenous retroviruses is dependent on DAXX, but not on ATRX. In support, we reveal the existence of two biochemically distinct DAXX-containing complexes: the ATRX–DAXX complex involved in gene repression and telomere chromatin structure, and a DAXX–SETDB1–KAP1–HDAC1 complex that represses endogenous retroviruses independently of ATRX and H3.3 incorporation into chromatin. We find that histone H3.3 stabilizes DAXX protein levels and can affect DAXX-regulated gene expression without incorporation into nucleosomes. Our study demonstrates a nucleosome-independent function for the H3.3 histone variant.

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [1];  [3]; ORCiD logo [1]
  1. Univ. of Wisconsin, Madison, WI (United States)
  2. South Univ. of Science and Technology, Guangdong (China); Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
  3. Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE; Neuroendocrine Tumor Research Foundation; Leukemia and Lymphoma Society; STARR Foundation; Memorial Sloan-Kettering Cancer Center; NIGMS
OSTI Identifier:
1430321
Grant/Contract Number:  
[AC02-06CH11357; P30 CA008748; P41 GM103403]
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
[ Journal Volume: 8; Journal Issue: 1]; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Embryonic stem cells; Histone variants; Nucleosomes; X-ray crystallography

Citation Formats

Hoelper, Dominik, Huang, Hongda, Jain, Aayushi Y., Patel, Dinshaw J., and Lewis, Peter W. Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX. United States: N. p., 2017. Web. doi:10.1038/s41467-017-01206-y.
Hoelper, Dominik, Huang, Hongda, Jain, Aayushi Y., Patel, Dinshaw J., & Lewis, Peter W. Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX. United States. doi:10.1038/s41467-017-01206-y.
Hoelper, Dominik, Huang, Hongda, Jain, Aayushi Y., Patel, Dinshaw J., and Lewis, Peter W. Mon . "Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX". United States. doi:10.1038/s41467-017-01206-y. https://www.osti.gov/servlets/purl/1430321.
@article{osti_1430321,
title = {Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX},
author = {Hoelper, Dominik and Huang, Hongda and Jain, Aayushi Y. and Patel, Dinshaw J. and Lewis, Peter W.},
abstractNote = {The ATRX–DAXX histone chaperone complex incorporates the histone variant H3.3 at heterochromatic regions in a replication-independent manner. Here, we present a high-resolution x-ray crystal structure of an interaction surface between ATRX and DAXX. We use single amino acid substitutions in DAXX that abrogate formation of the complex to explore ATRX-dependent and ATRX-independent functions of DAXX. We find that the repression of specific murine endogenous retroviruses is dependent on DAXX, but not on ATRX. In support, we reveal the existence of two biochemically distinct DAXX-containing complexes: the ATRX–DAXX complex involved in gene repression and telomere chromatin structure, and a DAXX–SETDB1–KAP1–HDAC1 complex that represses endogenous retroviruses independently of ATRX and H3.3 incorporation into chromatin. We find that histone H3.3 stabilizes DAXX protein levels and can affect DAXX-regulated gene expression without incorporation into nucleosomes. Our study demonstrates a nucleosome-independent function for the H3.3 histone variant.},
doi = {10.1038/s41467-017-01206-y},
journal = {Nature Communications},
number = [1],
volume = [8],
place = {United States},
year = {2017},
month = {10}
}

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Works referenced in this record:

Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET
journal, February 2010

  • Matsui, Toshiyuki; Leung, Danny; Miyashita, Hiroki
  • Nature, Vol. 464, Issue 7290
  • DOI: 10.1038/nature08858

Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing
journal, January 2012

  • Ding, Li; Ley, Timothy J.; Larson, David E.
  • Nature, Vol. 481, Issue 7382
  • DOI: 10.1038/nature10738

DAXX co-folds with H3.3/H4 using high local stability conferred by the H3.3 variant recognition residues
journal, January 2014

  • DeNizio, Jamie E.; Elsässer, Simon J.; Black, Ben E.
  • Nucleic Acids Research, Vol. 42, Issue 7
  • DOI: 10.1093/nar/gku090

The Histone Variant H3.3 Marks Active Chromatin by Replication-Independent Nucleosome Assembly
journal, June 2002


ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome
journal, June 2011

  • Iwase, Shigeki; Xiang, Bin; Ghosh, Sharmistha
  • Nature Structural & Molecular Biology, Vol. 18, Issue 7
  • DOI: 10.1038/nsmb.2062

Thermodynamic Stability of Histone H3 Is a Necessary but not Sufficient Driving Force for its Evolutionary Conservation
journal, January 2011


The double face of the histone variant H3.3
journal, January 2011

  • Szenker, Emmanuelle; Ray-Gallet, Dominique; Almouzni, Geneviève
  • Cell Research, Vol. 21, Issue 3
  • DOI: 10.1038/cr.2011.14

EBSeq: an empirical Bayes hierarchical model for inference in RNA-seq experiments
journal, February 2013


DAXX envelops a histone H3.3–H4 dimer for H3.3-specific recognition
journal, October 2012

  • Elsässer, Simon J.; Huang, Hongda; Lewis, Peter W.
  • Nature, Vol. 491, Issue 7425
  • DOI: 10.1038/nature11608

Aberrant Overexpression of Satellite Repeats in Pancreatic and Other Epithelial Cancers
journal, January 2011


PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Required for Gene Silencing
journal, December 2007


DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors
journal, January 2011


Critical role for Daxx in regulating Mdm2
journal, July 2006

  • Tang, Jun; Qu, Li-Ke; Zhang, Jianke
  • Nature Cell Biology, Vol. 8, Issue 8
  • DOI: 10.1038/ncb1442

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing
journal, May 2008

  • Zeng, Lei; Yap, Kyoko L.; Ivanov, Alexey V.
  • Nature Structural & Molecular Biology, Vol. 15, Issue 6
  • DOI: 10.1038/nsmb.1416

Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions
journal, March 2010


Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation
journal, March 2008


Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development
journal, August 1999


Differential expression analysis for sequence count data
journal, October 2010


Dynamic control of endogenous retroviruses during development
journal, March 2011


Daxx: death or survival protein?
journal, February 2006


Histone Variants in Metazoan Development
journal, November 2010


Serine 31 phosphorylation of histone variant H3.3 is specific to regions bordering centromeres in metaphase chromosomes
journal, April 2005

  • Hake, S. B.; Garcia, B. A.; Kauer, M.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 18
  • DOI: 10.1073/pnas.0502413102

Atrx promotes heterochromatin formation at retrotransposons
journal, May 2015


Histone H3.1 and H3.3 Complexes Mediate Nucleosome Assembly Pathways Dependent or Independent of DNA Synthesis
journal, January 2004


ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells
journal, January 2010


The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis
journal, January 2005

  • Bérubé, Nathalie G.; Mangelsdorf, Marie; Jagla, Magdalena
  • Journal of Clinical Investigation, Vol. 115, Issue 2
  • DOI: 10.1172/JCI200522329

TRIM28 Controls a Gene Regulatory Network Based on Endogenous Retroviruses in Human Neural Progenitor Cells
journal, January 2017


Association of Age at Diagnosis and Genetic Mutations in Patients With Neuroblastoma
journal, March 2012


A Novel Transcription Regulatory Complex Containing Death Domain-associated Protein and the ATR-X Syndrome Protein
journal, February 2004

  • Tang, Jun; Wu, Shaobo; Liu, Hongtu
  • Journal of Biological Chemistry, Vol. 279, Issue 19
  • DOI: 10.1074/jbc.M401321200

Hira-Dependent Histone H3.3 Deposition Facilitates PRC2 Recruitment at Developmental Loci in ES Cells
journal, September 2013


ATRX promotes gene expression by facilitating transcriptional elongation through guanine-rich coding regions
journal, December 2014

  • Levy, Michael A.; Kernohan, Kristin D.; Jiang, Yan
  • Human Molecular Genetics, Vol. 24, Issue 7
  • DOI: 10.1093/hmg/ddu596

Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells
journal, May 2015

  • Elsässer, Simon J.; Noh, Kyung-Min; Diaz, Nichole
  • Nature, Vol. 522, Issue 7555
  • DOI: 10.1038/nature14345

The enemy within: An epigenetic role of retrotransposons in cancer initiation
journal, August 2010


Release of RASSF1C from the nucleus by Daxx degradation links DNA damage and SAPK/JNK activation
journal, June 2006


Altered Telomeres in Tumors with ATRX and DAXX Mutations
journal, June 2011


The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3
journal, May 2010

  • Drane, P.; Ouararhni, K.; Depaux, A.
  • Genes & Development, Vol. 24, Issue 12
  • DOI: 10.1101/gad.566910

Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres
journal, July 2010

  • Lewis, P. W.; Elsaesser, S. J.; Noh, K. -M.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 32
  • DOI: 10.1073/pnas.1008850107

Transposable elements and the evolution of regulatory networks
journal, May 2008

  • Feschotte, Cédric
  • Nature Reviews Genetics, Vol. 9, Issue 5
  • DOI: 10.1038/nrg2337

Structure of the variant histone H3.3–H4 heterodimer in complex with its chaperone DAXX
journal, November 2012

  • Liu, Chao-Pei; Xiong, Chaoyang; Wang, Mingzhu
  • Nature Structural & Molecular Biology, Vol. 19, Issue 12
  • DOI: 10.1038/nsmb.2439

Structural and Functional Roles of Daxx SIM Phosphorylation in SUMO Paralog-Selective Binding and Apoptosis Modulation
journal, April 2011


Developmental roles of histone H3 variants and their chaperones
journal, November 2013

  • Filipescu, Dan; Szenker, Emmanuelle; Almouzni, Geneviève
  • Trends in Genetics, Vol. 29, Issue 11
  • DOI: 10.1016/j.tig.2013.06.002

Sequestration and Inhibition of Daxx-Mediated Transcriptional Repression by PML
journal, March 2000


KAP1 controls endogenous retroviruses in embryonic stem cells
journal, January 2010

  • Rowe, Helen M.; Jakobsson, Johan; Mesnard, Daniel
  • Nature, Vol. 463, Issue 7278
  • DOI: 10.1038/nature08674

Structural Characterization of the DAXX N-Terminal Helical Bundle Domain and Its Complex with Rassf1C
journal, December 2010


Landscape of Somatic Retrotransposition in Human Cancers
journal, June 2012


Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway
journal, July 2012