Multiple personalities: competitive binding of NuRD subunits can lead to distinct functions

Low JKK1, Silva APG1, Sharifi-Tabar M1, Torrado M1, Sana M1, Parker BL1, Shepherd NE1, Landsberg MJ2 and Mackay JP1

  1. School of Life and Environmental Sciences, University of Sydney, NSW, Australia.
  2. School of Chemistry and Molecular Biosciences, The University of Queensland, QLD, Australia.

The Nucleosome Remodeling and Deacetylase (NuRD) complex is a ~1-MDa 10-subunit transcriptional co-regulator that plays essential roles in normal development, stem cell renewal and DNA repair. A detailed understanding, however, of NuRD structure and function has proven to be challenging. Using a barrage of biochemical and biophysical techniques, we demonstrate that the NuRD complex is made up of two modules of roughly equal size: (i) a symmetric ~450 kDa MTA-HDAC-RBBP (MHR) module carrying the deacetylase activity driven by its HDAC component; and (ii) an asymmetric ~320 kDa MBD-GATAD2-CHD (mGC) module carrying the remodelling activity driven by its CHD component. This bifurcation of the two enzymatic activities into apparently stable modules is intriguing; especially in the light of new observations that another transcriptional co-regulator can compete directly with the mGC module for binding to MHR. This transcriptional co-regulator selectively recruits the MHR module to gene promoters to influence histone acetylation levels. Isoform-specific functions of NuRD have been previously described; MBD2- and MBD3-NuRD target different promoters, and CHD3-, CHD4-, CHD5-NuRD have distinct roles in cortical development. However, the MHR and mGC modules as separate entities, upon which other complexes are built upon (for MHR at least), are yet to be appreciated. It is possible the NuRD complex (and its isoform-specific versions) may in fact be just one example out of the many possible combinations of MHR-based complexes, and that each of these complexes have distinct functions and targets in the cell.