Moonlighting with WDR5: A Cellular Multitasker

Abstract

WDR5 is a highly conserved WD40 repeat-containing protein that is essential for proper regulation of multiple cellular processes. WDR5 is best characterized as a core scaffolding component of histone methyltransferase complexes, but emerging evidence demonstrates that it does much more, ranging from expanded functions in the nucleus through to controlling the integrity of cell division. The purpose of this review is to describe the current molecular understandings of WDR5, discuss how it participates in diverse cellular processes, and highlight drug discovery efforts around WDR5 that may form the basis of new anti-cancer therapies.

KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

“…The most highly expressed of these subunits is WDR5, a WD40 repeat-containing protein that contains two key interaction domains (Win, WDR5interacting site; WBM, WDR5-binding motif). The WDR5 Win domain binds a conserved Win interaction motif (WIM) found on all KMT2 proteins [13,14], whereas the WBM domain facilitates WDR5 binding to the RBBP5 core subunit (as well as other nuclear proteins and transcription factors) [15,16]. The WDR5 Win domain also acts as a histone reader specific for the H3R2me2 marker associated with chromatin "poised" for transcription.…”

Polycomb/Trithorax Antagonism: Cellular Memory in Stem Cell Fate and Function

“…For instance, KMT2A and KMT2B subunits of the Trx-COMPASS complex both possess a CXXC domain that binds to non-methylated CpG islands, whereas the Cfp1 subunit of Set1-COMPASS serves the same purpose (Lee et al, 2007). Other examples include WDR5, a protein present in all COMPASS complexes, that recognizes the H3R2me2s (Guarnaccia and Tansey, 2018), as well as the BRG1 (or BRM) and BAF180 subunits of SWI/SNF that all possess bromodomains, allowing stabilization of binding to acetylated histone H3 (Charlop-Powers et al, 2010;Shen et al, 2007).…”

Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity

“…One epigenetic regulator that has received considerable attention as a cancer target is WDR5. WDR5 is a WD40-repeat protein that scaffolds the assembly of multiple epigenetic “writers,” including the non-specific lethal (NSL) and Ada2-containing (ATAC) histone acetyltransferase (HAT) complexes and the MLL/SET-type histone methyltransferases (HMTs) that catalyze histone H3 lysine 4 (H3K4) di- and tri-methylation ( Guarnaccia and Tansey, 2018 ). Aberrant WDR5 expression is implicated in a variety of cancers, such as leukemias ( Ge et al, 2016 ), breast cancer ( Dai et al, 2015 ), and bladder cancer ( Chen et al, 2015 ).…”

“…From a structural perspective, the most obvious route to pharmacologically inhibit WDR5 is via the WIN (WDR5 interaction) site, a well-defined pocket that mediates interaction with an arginine-containing motif (WIN motif; consensus “ARA”) present in multiple WDR5-interaction partners ( Guarnaccia and Tansey, 2018 ). Although the functions of the WIN site are not fully understood, it is clear that the HMT activity of complexes carrying the MLL1 protein, but not other mixed lineage leukemia/Su(var)3–9, Ezh2, Trithorax (MLL/SET) family members, is dependent on WIN site binding by a WIN motif ( Alicea-Velázquez et al, 2016 ), leading to the concept that WIN site inhibitors could alter transcriptional patterns by modulating H3K4 methylation.…”