Cancer biology and NuRD: a multifaceted chromatin remodelling complex

Abstract

The nucleosome remodelling and histone deacetylase (NuRD; also known as Mi-2) complex regulates gene expression at the level of chromatin. The NuRD complex has been identified - using both genetic and molecular analyses - as a key determinant of differentiation in mouse embryonic stem cells and during development in various model systems. Similar to other chromatin remodellers, such as SWI/SNF and Polycomb complexes, NuRD has also been implicated in the regulation of transcriptional events that are integral to oncogenesis and cancer progression. Emerging molecular details regarding the recruitment of NuRD to specific loci during development, and the modulation of these events in cancer, are used to illustrate how the inappropriate localization of the complex could contribute to tumour biology.

Figure 1. Core components of the NuRD complex

Conserved protein domains and known functions within the complex are shown for each NuRD subunit and their variants. The CHD3/CHD4 subunit consists of 2 PHD fingers, 2 chromodomains, and an ATPase domain. The PHD fingers are required for interaction with HDAC1 and for modified histone tails^,. The chromodomains display DNA binding activity and are indispensable for ATPase, nucleosome mobilization, and nucleosome binding. The ATPase domain carries out ATP hydrolysis which provides the energy necessary for remodeling nucleosome by either histone displacement^, or histone octamer sliding. HDAC1/2 are class I HDACS that share homology to the yeast RPD3 gene and consist of a zinc containing deacetylase catalytic domain. HDAC1 and HDAC2 uniquely contain an additional C terminal Rb binding motif. MBD2 and MBD3 contain a conserved MBD motif. The MBD domain of MBD2 but not MBD3 binds methylated DNA^,. MBD2 also contains a glycine and arginine (GR) rich region and a transcriptional repression domain (TRD) involved in recruiting HDAC^,. MBD3 contains a glutamate (G) repeat region near the C-terminus. MTA1/2/3 share four highly conserved functional domains including the bromo-adjacent homology (BAH) domain, the Egl27/MTA1 (ELM) domain, the SW13, ADA2, N-CoR and TFIII B B” (SANT) domain, and a zinc finger DNA binding domain. The BAH domain is thought to be involved in protein-protein interaction, while the SANT domain seems to contribute to MTA2-HDAC1 interaction. The zinc finger domain has been shown to be necessary for interaction with transcription factors or transcriptional co-regulators such as FOG-2. Function of the ELM domain of MTA proteins remains undefined. p66a/b contain 2 conserved regions. The amino terminal conserved region directly interact with MBD2 or MBD3, while the carboxyl terminal conserved region can interact with histone tails and is important for targeting to specific genomic loci^,. Both RbAp46 and RbAp48 contain 6 WD-40 repeats which fold into a seven-bladed b propeller structure and binds to histone H4.

Figure 2. Mechanisms by which the NuRD complex interacts with the different factors to promote cancer development

A. Recruitment of NuRD complex by tissue-specific transcription factor to gene promoters to mediate transcriptional repression. Several known oncogenes have been shown to recruit the NuRD complex to suppress transcription of tumor suppressor genes. B. Post-translational modification of transcription factor by NuRD complex to modulate downstream transcriptional activities. In hypoxic breast cancer cells, MTA1 recruits HDAC1 to promote deacetylation of HIF1α, leading to stabilization of HIF1α and its transcriptional program. Conversely, deacetylation of p53 by the NuRD complex results in inactivation of p53, rendering cells resistant to cell growth arrest and apoptosis^,. C. An MBD2 containing NuRD complex targeting hypermethylated promoters of tumor suppressor genes to mediate transcriptional silencing^-.

Figure 3. Non-transcriptional mechanisms by which NuRD complex maintain genome stability

A. Co-localization of the NuRD complex with DNA replication machineries such as CAF1 and PCNA during the S phase of the cell cycle suggests a role of the complex in chromatin assembly during and/or post DNA replication. B. NuRD complex promoting G1/S phase transition during cell cycle progression by promoting deacetylation of p53. Loss of p53 function results in inactivation of p21 to allow cell cycle progression. C. Recruitment of NuRD complex to site of DNA damage to facilitate the DNA repair process. At sites of double-stranded breaks, PARP incorporates poly (ADP ribose) chains that can recruit the NuRD complex in addition to other DNA repair proteins to facilitate the repair process^,.