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Multivalent Histone and DNA Engagement by a PHD/BRD/PWWP Triple Reader Cassette Recruits ZMYND8 to K14ac-Rich Chromatin.

Cell reports | 2016

Elucidation of interactions involving DNA and histone post-translational-modifications (PTMs) is essential for providing insights into complex biological functions. Reader assemblies connected by flexible linkages facilitate avidity and increase affinity; however, little is known about the contribution to the recognition process of multiple PTMs because of rigidity in the absence of conformational flexibility. Here, we resolve the crystal structure of the triple reader module (PHD-BRD-PWWP) of ZMYND8, which forms a stable unit capable of simultaneously recognizing multiple histone PTMs while presenting a charged platform for association with DNA. Single domain disruptions destroy the functional network of interactions initiated by ZMYND8, impairing recruitment to sites of DNA damage. Our data establish a proof of principle that rigidity can be compensated by concomitant DNA and histone PTM interactions, maintaining multivalent engagement of transient chromatin states. Thus, our findings demonstrate an important role for rigid multivalent reader modules in nucleosome binding and chromatin function.

Pubmed ID: 27926874 RIS Download

Research resources used in this publication

None found

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Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM068088
  • Agency: CIHR, Canada
    Id: FDN 143301
  • Agency: Wellcome Trust, United Kingdom
    Id: 095751/Z/11/Z
  • Agency: Wellcome Trust, United Kingdom
    Id: 090532/Z/09/Z
  • Agency: Wellcome Trust, United Kingdom
    Id: 092809/Z/10/Z
  • Agency: Medical Research Council, United Kingdom
    Id: MR/N010051/1
  • Agency: NIGMS NIH HHS, United States
    Id: K12 GM000678

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RRID:SCR_002760

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