Loss of the E3 ubiquitin ligases UBR-5 or HECD-1 restores <i>Caenorhabditis elegans</i> development in the absence of SWI/SNF function.

Abstract

SWItch/sucrose non-fermenting (SWI/SNF) complexes are a family of chromatin remodelers that are conserved across eukaryotes. Mutations in subunits of SWI/SNF cause a multitude of different developmental disorders in humans, most of which have no current treatment options. Here, we identify an alanine-to-valine-causing mutation in the SWI/SNF subunit <i>snfc-5</i> (<i>SMARCB1</i> in humans) that prevents embryonic lethality in <i>Caenorhabditis elegans</i> nematodes harboring a loss-of-function mutation in the SWI/SNF subunit <i>swsn-1</i> (<i>SMARCC1/2</i> in humans). Furthermore, we found that the combination of this specific mutation in <i>snfc-5</i> and a loss-of-function mutation in either of the E3 ubiquitin ligases <i>ubr-5</i> (<i>UBR5</i> in humans) or <i>hecd-1</i> (<i>HECTD1</i> in humans) can restore development to adulthood in <i>swsn-1</i> loss-of-function mutants that otherwise die as embryos. Using these mutant models, we established a set of 335 genes that are dysregulated in SWI/SNF mutants that arrest their development embryonically but exhibit near wild-type levels of expression in the presence of suppressor mutations that prevent embryonic lethality, suggesting that SWI/SNF promotes development by regulating some subset of these 335 genes. In addition, we show that SWI/SNF protein levels are reduced in <i>swsn-1; snfc-5</i> double mutants and partly restored to wild-type levels in <i>swsn-1; snfc-5; ubr-5</i> triple mutants, consistent with a model in which UBR-5 regulates SWI/SNF levels by tagging the complex for proteasomal degradation. Our findings establish a link between two E3 ubiquitin ligases and SWI/SNF function and suggest that UBR5 and HECTD1 could be potential therapeutic targets for the many developmental disorders caused by missense mutations in SWI/SNF subunits.