Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting

Mol Cell. 2013 Mar 7;49(5):843-57. doi: 10.1016/j.molcel.2012.12.006. Epub 2013 Jan 11.


Bromodomain-containing protein 4 (Brd4) is an epigenetic reader and transcriptional regulator recently identified as a cancer therapeutic target for acute myeloid leukemia, multiple myeloma, and Burkitt's lymphoma. Although chromatin targeting is a crucial function of Brd4, there is little understanding of how bromodomains that bind acetylated histones are regulated, nor how the gene-specific activity of Brd4 is determined. Via interaction screen and domain mapping, we identified p53 as a functional partner of Brd4. Interestingly, Brd4 association with p53 is modulated by casein kinase II (CK2)-mediated phosphorylation of a conserved acidic region in Brd4 that selectively contacts either a juxtaposed bromodomain or an adjacent basic region to dictate the ability of Brd4 binding to chromatin and also the recruitment of p53 to regulated promoters. The unmasking of bromodomains and activator recruitment, concurrently triggered by the CK2 phospho switch, provide an intriguing mechanism for gene-specific targeting by a universal epigenetic reader.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism*
  • Cell Cycle Proteins
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Gene Targeting*
  • HCT116 Cells
  • HEK293 Cells
  • Histones / chemistry
  • Histones / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Histones
  • Nuclear Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Casein Kinase II