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

Abstract

The 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 in numerous biological processes in multiple organs has been well established in mouse knockout models. The phenotype of the first monoallelic germ line missense mutation in the 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.

Bcl11 Transcription Factors Regulate Cortical Development and Function

“…In addition to the C2H2 zinc-finger domains located on exon 4 of both genes, Bcl11 proteins contain several protein-protein interacting domains at their N-terminal end like the nucleosome remodeling and deacetylase (NuRD) interacting domain and a CCHC finger motif (Figure 1; Liu et al, 2006). The CCHC motif unlike the DNA-binding C2H2 motif promotes dimerization and nuclear translocation allowing the transcriptional regulation of target genes as was shown for Bcl11b (Grabarczyk et al, 2018). Furthermore, analysis of heterozygous mutations of the human CCHC finger motif strongly suggests that Bcl11b functions as a dimer (Grabarczyk et al, 2018).…”

“…The CCHC motif unlike the DNA-binding C2H2 motif promotes dimerization and nuclear translocation allowing the transcriptional regulation of target genes as was shown for Bcl11b (Grabarczyk et al, 2018). Furthermore, analysis of heterozygous mutations of the human CCHC finger motif strongly suggests that Bcl11b functions as a dimer (Grabarczyk et al, 2018). Although no data are available so far it is most likely that the CCHC motif has a similar function for Bcl11a protein regulation.…”

Genome-Wide Association Studies for Immunoglobulins in Colostrum and Serum in Chinese Holstein

“…It is worth mentioning that AKT1 was also identi ed as candidate gene for IgG1 in a previous study [20]. BCL11B encodes a C2H2-type zinc nger protein that regulates the initial stages of human T-cell differentiation and mediated epigenetic repression for histone deacetylase inhibitors in cutaneous T-Cell lymphoma [43][44][45]. HHIPL1 belongs to the glucose/sorbosone dehydrogenase family and take part in receptor-mediated endocytosis so that it can effect receptor activity.…”

Genome-Wide Association Studies for Immunoglobulin Concentrations in Colostrum and Serum in Chinese Holstein

“…BCL11B encodes a C2H2-type zinc nger protein, that a key regulator in the initial stages of human T-cell differentiation [45]. Previous studies discovered that BCL11B induced cell cycle arrest and protected against DNA damage-driven apoptosis [46,47]. The protein encoded by HHIPL1 is a secreted protein belonging to the glucose/sorbosone dehydrogenase family.…”