Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA

John K. Lee, Darko Bosnakovski, Erik A. Toso, Tracy Dinh, Surajit Banerjee, Thomas E. Bohl, Ke Shi, Kayo Orellana, Michael Kyba, Hideki Aihara

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Double homeobox (DUX) transcription factors are unique to eutherian mammals. DUX4 regulates expression of repetitive elements during early embryogenesis, but misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and translocations overexpressing the DUX4 double homeodomain cause B cell leukemia. Here, we report the crystal structure of the tandem homeodomains of DUX4 bound to DNA. The homeodomains bind DNA in a head-to-head fashion, with the linker making anchoring DNA minor-groove interactions and unique protein contacts. Remarkably, despite being tandem duplicates, the DUX4 homeodomains recognize different core sequences. This results from an arginine-to-glutamate mutation, unique to primates, causing alternative positioning of a key arginine side chain in the recognition helix. Mutational studies demonstrate that this primate-specific change is responsible for the divergence in sequence recognition that likely drove coevolution of embryonically regulated repeats in primates. Our work provides a framework for understanding the endogenous function of DUX4 and its role in FSHD and cancer. Lee et al. determine the crystal structure of the facioscapulohumeral muscular dystrophy and cancer-associated transcription factor DUX4, bound to DNA. The structure gives insight into how the double homeodomain of DUX4, which is related by duplication of an ancestral homeodomain, has evolved different sequence specificities, uniquely in the primate lineage.

Original languageEnglish (US)
Pages (from-to)2955-2962.e3
JournalCell reports
Volume25
Issue number11
DOIs
StatePublished - Dec 11 2018

Bibliographical note

Funding Information:
We thank Cynthia S. Faraday for graphic design. This work was supported by grants from the Friends of FSH Research and NIH (R35 GM118047 to H.A.; R01 AR055685 to M.K.). This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by NIH (NIGMS P30-GM124165). The Pilatus 6M detector on 24-ID-C beamline is funded by a NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Funding Information:
We thank Cynthia S. Faraday for graphic design. This work was supported by grants from the Friends of FSH Research and NIH ( R35 GM118047 to H.A.; R01 AR055685 to M.K.). This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by NIH ( NIGMS P30-GM124165 ). The Pilatus 6M detector on 24-ID-C beamline is funded by a NIH-ORIP HEI grant ( S10 RR029205 ). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357 .

Publisher Copyright:
© 2018 The Author(s)

Keywords

  • B cell leukemia
  • DNA sequence readout
  • DUX
  • FSHD
  • cleavage stage development
  • crystal structure
  • double homeobox
  • facioscapulohumeral muscular dystrophy
  • retrovirus-like elements
  • tandem homeodomains

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