The N-Terminal CCHC Zinc Finger Motif Mediates Homodimerization of Transcription Factor BCL11B

Mol Cell Biol. 2018 Feb 12;38(5):e00368-17. doi: 10.1128/MCB.00368-17. Print 2018 Mar 1.


The BCL11B gene encodes a Krüppel-like, sequence-specific zinc finger (ZF) transcription factor that acts as either a repressor or an activator, depending on its posttranslational modifications. The importance of BCL11B in numerous biological processes in multiple organs has been well established in mouse knockout models. The phenotype of the first de novo monoallelic germ line missense mutation in the BCL11B gene (encoding N441K) strongly implies that the mutant protein acts in a dominant-negative manner by neutralizing the unaffected protein through the formation of a nonfunctional dimer. Using a Förster resonance energy transfer-assisted fluorescence-activated cell sorting (FACS-FRET) assay and affinity purification followed by mass spectrometry (AP-MS), we show that the N-terminal CCHC zinc finger motif is necessary and sufficient for the formation of the BCL11B dimer. Mutation of the CCHC ZF in BCL11B abolishes its transcription-regulatory activity. In addition, unlike wild-type BCL11B, this mutant is incapable of inducing cell cycle arrest and protecting against DNA damage-driven apoptosis. Our results confirm the BCL11B dimerization hypothesis and prove its importance for BCL11B function. By mapping the relevant regions to the CCHC domain, we describe a previously unidentified mechanism of transcription factor homodimerization.

Keywords: FRET; apoptosis; cell cycle; chromatin remodeling; mass spectrometry; protein-protein interactions; transcription factors; transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Culture Techniques
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Fluorescence Resonance Energy Transfer / methods
  • Germ-Line Mutation
  • Humans
  • Mass Spectrometry / methods
  • Mutation, Missense
  • Protein Domains
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*
  • Zinc Fingers


  • BCL11B protein, human
  • DNA-Binding Proteins
  • Repressor Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins