WDR46

WDR46 is a highly insoluble nucleolar scaffold protein that supports ribosome biogenesis by organizing factors required for small-subunit rRNA processing (PMID:23848194, PMID:24754225). Through its intrinsically disordered N- and C-terminal regions, it anchors itself within the dense fibrillar and granular compartments of the nucleolus and binds nucleolin, DDX21, NOP2, and EBP2; loss of WDR46 selectively mislocalizes the 18S rRNA processing factors nucleolin and DDX21 to the nucleolar periphery while leaving the 28S processing factors NOP2 and EBP2 intact, establishing WDR46 as a recruitment hub that re-establishes the granular component in daughter cells after division (PMID:23848194). FRAP measurements show a large, very-low-mobility WDR46 fraction tied to macro-protein complexes that is partly released when rRNA transcription is suppressed, consistent with a core structural role (PMID:24754225). The yeast ortholog Utp7 extends this function to the cell cycle, localizing to kinetochores and regulating Sli15 (INCENP) and Cdc14 phosphatase to restrain their premature release/concentration before anaphase, linking ribosome biogenesis to chromosome segregation (PMID:18794331), and in C. elegans loss of the ortholog activates SKN-1/Nrf detoxification gene expression via the p53 homolog CEP-1, defining a nucleolar-stress signaling output (PMID:22240150). In hepatocellular carcinoma, the HBV core protein stabilizes WDR46 by blocking TRIM25-mediated ubiquitination and promotes WDR46-dependent recruitment of c-Myc to the NUSAP1 promoter, driving tumor cell growth and migration (PMID:40366140).

1. 2008 High

   Whether a nucleolar WDR-repeat protein could couple ribosome biogenesis to mitotic control was unknown; characterization of the yeast ortholog Utp7 placed it at kinetochores regulating Sli15/INCENP and Cdc14, establishing a node connecting rRNA biogenesis with chromosome segregation.

   Evidence Reciprocal co-IP, genetic epistasis, localization and phosphorylation assays in S. cerevisiae

   PMID:18794331

   Open questions at the time

   • Kinetochore role demonstrated only in yeast, not shown for human WDR46
   • Mechanism by which Utp7 restrains Cdc14/Sli15 not resolved at molecular level
2. 2011 Medium

   It was unclear what cellular signaling follows disruption of nucleolar function; loss of the C. elegans ortholog was shown to activate the SKN-1/Nrf detoxification program partly through the p53 homolog CEP-1, defining a nucleolar-stress signaling output.

   Evidence RNAi, mutant allele analysis, genetic epistasis and reporter assays in C. elegans

   PMID:22240150

   Open questions at the time

   • Molecular link between nucleolar disruption and SKN-1 activation undefined
   • Conservation of this stress axis in mammals untested
3. 2013 Medium

   The molecular function of human WDR46 was unknown; knockdown and domain analysis showed it is an insoluble nucleolar scaffold whose disordered termini recruit nucleolin and DDX21 to selectively support 18S rRNA processing.

   Evidence siRNA knockdown, fluorescence microscopy, domain deletion, co-IP of binding partners in human cells

   PMID:23848194

   Open questions at the time

   • Direct vs indirect binding to each partner not distinguished
   • Effect on mature 18S rRNA yield not quantified
4. 2014 Medium

   The dynamic behavior of WDR46 in the nucleolus was unknown; live-cell imaging with FRAP demonstrated a large immobile fraction tied to macro-protein complexes that is partly mobilized when rRNA transcription stops, supporting a core scaffold role.

   Evidence GFP-fusion live-cell imaging and FRAP in HeLa cells with transcription suppression

   PMID:24754225

   Open questions at the time

   • Identity of the complexes constraining mobility not defined
   • Single cell line
5. 2025 Medium

   Whether WDR46 contributes to disease was unaddressed; in HCC the HBV core protein stabilizes WDR46 by blocking TRIM25-mediated ubiquitination and routes it to co-activate c-Myc at the NUSAP1 promoter, driving tumor growth and migration.

   Evidence Co-IP, ChIP, ubiquitination assays, in vitro and in vivo oncology assays

   PMID:40366140

   Open questions at the time

   • Direct WDR46–c-Myc binding interface not mapped
   • Whether transcriptional role is separable from nucleolar scaffold function unclear

• How WDR46's nucleolar scaffold function mechanistically integrates with its cell-cycle (kinetochore) and transcriptional (c-Myc) activities in human cells remains unresolved.
• No structural model of WDR46 within the SSU processome
• Human kinetochore association not tested
• Substrate/target specificity of its disordered recruitment regions undefined