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Cited by 12Protein Degradation and InhibitorsChromatin Remodeling and CancerGenomics and Chromatin Dynamics

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Oncogenic Truncations of ASXL1 Enhance a Motif for BRD4 ET-Domain Binding

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Burgess, Abigail E., Kleffmann, Torsten, Mace, Peter D.·2021·Journal of Molecular Biology
DOI 10.1016/j.jmb.2021.167242

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Abstract

Abstract Proper regulation of gene-expression relies on specific protein-protein interactions between a myriad of epigenetic regulators. As such, mutation of genes encoding epigenetic regulators often drive cancer and developmental disorders. Additional sex combs-like protein 1 (ASXL1) is a key example, where mutations frequently drive haematological cancers and can cause developmental disorders. It has been reported that nonsense mutations in ASXL1 promote an interaction with BRD4, another central epigenetic regulator. Here we provide a molecular mechanism for the BRD4-ASXL1 interaction, demonstrating that a motif near to common truncation breakpoints of ASXL1 contains an epitope that binds the ET domain within BRD4. Binding-studies show that this interaction is analogous to common ET-binding modes of BRD4-interactors, and that all three ASX-like protein orthologs (ASXL1–3) contain a functional ET-domain-binding epitope. Crucially, we observe that BRD4-ASXL1 binding is markedly increased in the prevalent ASXL1 Y591X truncation that maintains the BRD4-binding epitope, relative to full-length ASXL1 or truncated proteins that delete the epitope. Together, these results show that ASXL1 truncation enhances BRD4 recruitment to transcriptional complexes via its ET domain, which could misdirect regulatory activity of either BRD4 or ASXL1 and may inform potential therapeutic interventions.

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Research works printed but not linked: 51

  1. Reddington, 2020, Molecular Regulation of the Polycomb Repressive-Deubiquitinase, Int. J. Mol. Sci., 21, 7837, 10.3390/ijms21217837 · DOI
  2. Chittock, 2017, Molecular architecture of polycomb repressive complexes, Biochem. Soc. Trans., 45, 193, 10.1042/BST20160173 · DOI
  3. Scheuermann, 2010, Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB, Nature., 465, 243, 10.1038/nature08966 · DOI
  4. Sahtoe, 2016, BAP1/ASXL1 recruitment and activation for H2A deubiquitination, Nature Commun., 7, 10292, 10.1038/ncomms10292 · DOI
  5. Foglizzo, 2018, A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes, Nature Commun., 9, 3932, 10.1038/s41467-018-06186-1 · DOI
  6. De, 2018, Structural Basis for the Activation of the Deubiquitinase Calypso by the Polycomb Protein ASX, Structure
  7. Carbone, 2013, BAP1 and cancer, Nature Rev. Cancer, 13, 153, 10.1038/nrc3459 · DOI
  8. Wiesner, 2011, Germline mutations in BAP1 predispose to melanocytic tumors, Nature Genet., 43, 1018, 10.1038/ng.910 · DOI
  9. Testa, 2011, Germline BAP1 mutations predispose to malignant mesothelioma, Nature Genet., 43, 1022, 10.1038/ng.912 · DOI · Paper page
  10. Balasubramani, 2015, Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex, Nature Commun., 6, 7307, 10.1038/ncomms8307 · DOI
  11. Gelsi-Boyer, 2012, Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases, J. Hematol. Oncol., 5, 12, 10.1186/1756-8722-5-12 · DOI
  12. Abdel-Wahab, 2012, ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression, Cancer Cell., 22, 180, 10.1016/j.ccr.2012.06.032 · DOI
  13. Micol, 2017, ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia, Nature Commun., 8, 15429, 10.1038/ncomms15429 · DOI
  14. Asada, 2018, Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis, Nature Commun., 9, 2733, 10.1038/s41467-018-05085-9 · DOI
  15. Inoue, 2013, Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations, J. Clin. Invest., 123, 4627, 10.1172/JCI70739 · DOI
  16. Asada, 2019, The role of ASXL1 in hematopoiesis and myeloid malignancies, Cell. Mol. Life Sci., 76, 2511, 10.1007/s00018-019-03084-7 · DOI
  17. Gao, 2013, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal, Sci. Signal, 6, 10.1126/scisignal.2004088 · DOI · Paper page
  18. Hoischen, 2011, De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome, Nature Genet., 43, 729, 10.1038/ng.868 · DOI
  19. Bainbridge, 2013, De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome, Genome Med., 5, 11, 10.1186/gm415 · DOI
  20. Shashi, 2016, De Novo truncating variants in ASXL2 are associated with a unique and recognizable clinical phenotype, Am. J. Hum. Genet., 99, 991, 10.1016/j.ajhg.2016.08.017 · DOI
  21. Nagase, 2018, Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation, J. Exp. Med., 215, 1729, 10.1084/jem.20171151 · DOI · Paper page
  22. Inoue, 2016, Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels, Exp. Hematol., 44, 10.1016/j.exphem.2015.11.011 · DOI
  23. Daou, 2018, Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1, Nature Commun., 9, 4385, 10.1038/s41467-018-06854-2 · DOI
  24. Yang, 2018, Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies, Blood, 131, 328, 10.1182/blood-2017-06-789669 · DOI
  25. Devaiah, 2016, BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin, Nature Struct. Mol. Biol., 23, 540, 10.1038/nsmb.3228 · DOI
  26. Dey, 2009, Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription, Mol. Biol. Cell., 20, 4899, 10.1091/mbc.e09-05-0380 · DOI
  27. Mochizuki, 2008, The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase, J. Biol. Chem., 283, 9040, 10.1074/jbc.M707603200 · DOI
  28. Yang, 2008, Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression, Mol. Cell. Biol., 28, 967, 10.1128/MCB.01020-07 · DOI
  29. Duan, 2018, Targeting Brd4 for cancer therapy: inhibitors and degraders, Medchemcomm, 9, 1779, 10.1039/C8MD00198G · DOI
  30. Szczepanski, 2020, ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer, Genome Med., 12, 63, 10.1186/s13073-020-00760-3 · DOI
  31. Wai, 2018, The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators, J. Biol. Chem., 293, 7160, 10.1074/jbc.RA117.000678 · DOI
  32. Zhang, 2016, Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4, Structure, 24, 1201, 10.1016/j.str.2016.04.019 · DOI
  33. Shen, 2015, NSD3-Short Is an Adaptor Protein that Couples BRD4 to the CHD8 Chromatin Remodeler, Mol. Cell., 60, 847, 10.1016/j.molcel.2015.10.033 · DOI
  34. Mirdita, 2021, ColabFold - Making protein folding accessible to all, BioRxiv
  35. Rahman, 2011, The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3, Mol. Cell. Biol., 31, 2641, 10.1128/MCB.01341-10 · DOI · Paper page
  36. Mann, 2021, Discovery of RSV-induced BRD4 protein interactions using native immunoprecipitation and Parallel Accumulation-Serial Fragmentation (PASEF) mass spectrometry, Viruses, 13, 454, 10.3390/v13030454 · DOI
  37. Dawson, 2011, Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia, Nature, 478, 529, 10.1038/nature10509 · DOI
  38. Lambert, 2019, Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains, Mol. Cell., 73, 621, 10.1016/j.molcel.2018.11.006 · DOI
  39. Branon, 2018, Efficient proximity labeling in living cells and organisms with TurboID, Nature Biotechnol., 36, 880, 10.1038/nbt.4201 · DOI · Paper page
  40. Wu, 2018, Brd4’s bromodomains mediate histone H3 acetylation and chromatin remodeling in pluripotent cells through P300 and Brg1, Cell Rep., 25, 1756, 10.1016/j.celrep.2018.10.003 · DOI
  41. Conrad, 2017, The short isoform of BRD4 promotes HIV-1 latency by engaging repressive SWI/SNF chromatin-remodeling complexes, Mol. Cell., 67, 10.1016/j.molcel.2017.07.025 · DOI
  42. Mellacheruvu, 2013, The CRAPome: a contaminant repository for affinity purification-mass spectrometry data, Nature Methods, 10, 730, 10.1038/nmeth.2557 · DOI · Paper page
  43. Shukla, 2017, ASXL3 is a novel pluripotency factor in human respiratory epithelial cells and a potential therapeutic target in small cell lung cancer, Cancer Res., 77, 6267, 10.1158/0008-5472.CAN-17-0570 · DOI
  44. Srivastava, 2016, De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome, Hum. Mol. Genet., 25, 597, 10.1093/hmg/ddv499 · DOI
  45. Bossone, 1992, MAZ, a zinc finger protein, binds to c-MYC and C2 gene sequences regulating transcriptional initiation and termination, Proc. Natl. Acad. Sci. U. S. A., 89, 7452, 10.1073/pnas.89.16.7452 · DOI
  46. Zhang, 2018, Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy, J. Clin. Invest., 128, 5383, 10.1172/JCI121366 · DOI
  47. Dey, 2012, Loss of the tumor suppressor BAP1 causes myeloid transformation, Science, 337, 1541, 10.1126/science.1221711 · DOI
  48. Jordan-Sciutto, 2000, Fetal Alz-50 clone 1 (FAC1) protein interacts with the Myc-associated zinc finger protein (ZF87/MAZ) and alters its transcriptional activity, Biochemistry, 39, 3206, 10.1021/bi992211q · DOI
  49. Wang, 2021, Epigenetic targeted therapy of stabilized BAP1 in ASXL1 gain-of-function mutated leukemia, Nature Cancer, 2, 515, 10.1038/s43018-021-00199-4 · DOI
  50. Käll, 2007, Semi-supervised learning for peptide identification from shotgun proteomics datasets, Nature Methods, 4, 923, 10.1038/nmeth1113 · DOI · Paper page
  51. Pettersen, 2021, UCSF ChimeraX: Structure visualization for researchers, educators, and developers, Protein Sci., 30, 70, 10.1002/pro.3943 · DOI

Metadata

Authors
Burgess, A. E., Kleffmann, T., & Mace, P. D.
Affiliations
University of Otago (NZ)
Corresponding author
Mace, Peter D.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2021-11
Volume
433
Issue
22
Pages
167242
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2021.167242
OpenAlex
W3199008733
Cited by
12
References
6
Citations by year
2026: 4 · 2025: 6 · 2024: 2
FWCI
0.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Health Research Council of New Zealand
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
ASXL1, BRD4, protein-protein interaction, nonsense mutation, epigenetic regulators, hematologic cancer, developmental disorders, transcriptional regulation, binding epitope
MeSH terms
Protein Domains, Gain of Function Mutation, Bromodomain Containing Proteins, Epitopes, Binding Sites, Humans, Repressor Proteins, Transcription Factors, Reproducibility of Results, Frameshift Mutation, Cell Cycle Proteins, Amino Acid Motifs, Multiprotein Complexes, HEK293 Cells

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