WDR5 is a conserved regulator of protein synthesis gene expression

Abstract

WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. WDR5 is also a promising target for pharmacological inhibition in cancer, with small molecule inhibitors of an arginine-binding pocket of WDR5 (the ‘WIN’ site) showing efficacy against a range of cancer cell lines in vitro. Efforts to understand WDR5, or establish the mechanism of action of WIN site inhibitors, however, are stymied by its many functions in the nucleus, and a lack of knowledge of the conserved gene networks—if any—that are under its control. Here, we have performed comparative genomic analyses to identify the conserved sites of WDR5 binding to chromatin, and the conserved genes regulated by WDR5, across a diverse panel of cancer cell lines. We show that a specific cohort of protein synthesis genes (PSGs) are invariantly bound by WDR5, demonstrate that the WIN site anchors WDR5 to chromatin at these sites, and establish that PSGs are bona fide, acute, and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and provide further evidence that WIN site inhibitors act to repress gene networks linked to protein synthesis homeostasis.

Impact of WIN site inhibitor on the WDR5 interactome

“…WDR5 is a conserved WD40-repeat protein that rose to prominence through its role in epigenetic complexes, including the KMT2 (MLL/SET) enzymes that deposit histone H3 lysine 4 (H3K4) methylation and the NSL (non-specific lethal) complex that lays down H4 lysine 16 acetylation. But WDR5 has functions outside these complexes, including recruiting MYC to chromatin ( Thomaset al, 2015 ), controlling expression of genes linkedto protein synthesis ( Bryan et al, 2020 ), enabling rapid gene reactivation upon exit from mitosis ( Oh et al, 2020 ), and promoting faithful assembly of the mitotic spindle ( Ali et al, 2017 ). Why and how WDR5 participates in so many processes are unclear, as is the extent to which its moonlighting capabilities have been revealed.…”

MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor–1

“…Fueled by reports that experimental inactivation of MYC promotes tumor regression in mice ( Alimova et al, 2019 ; Beaulieu et al, 2019 ; Giuriato et al, 2006 ; Jain, 2002 ; Soucek et al, 2013 ), there is considerable interest in the idea that MYC inhibitors could form the basis of broadly effective anticancer therapies. MYC itself, however, is widely viewed as undruggable ( Dang et al, 2017 ), meaning that effective strategies to pharmacologically inhibit MYC will most likely come from targeting the co-factors with which it interacts to drive and sustain the malignant state ( Brockmann et al, 2013 ; Bryan et al, 2020 ).…”

KDM6A mutations promote acute cytoplasmic DNA release, DNA damage response and mitosis defects

“…KDM4C, KDM1A and KDM7B have already been linked to mitosis by regulation of chromosome segregation, transcriptional activation of mitotic checkpoint complex components (see refs in (29)). Moreover, WDR5 and KMT proteins, likely KDM6A interaction partners, have also been shown to be involved in mitosis (31,32): WDR5 is part of the midbody in the spindle apparatus (30). Intriguingly, we found endogenous KDM6A, too, located along the midbody (Figure S11).…”