| Autor: |
Lampersberger L; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.; Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK., Conte F; Institute of Molecular Biology, Mainz 55128, Germany., Ghosh S; Medical Research Council London Institute of Medical Sciences, London W12 0NN, UK., Xiao Y; Department of Biochemistry and Cell Biology, Stony Brook University, NY 11790., Price J; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.; Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK., Jordan D; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.; Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK., Matus DQ; Department of Biochemistry and Cell Biology, Stony Brook University, NY 11790., Sarkies P; Medical Research Council London Institute of Medical Sciences, London W12 0NN, UK.; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK., Beli P; Institute of Molecular Biology, Mainz 55128, Germany., Miska EA; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.; Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.; Wellcome Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK., Burton NO; Department of Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503. |
| Abstrakt: |
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 snfc-5 ( SMARCB1 in humans) that prevents embryonic lethality in Caenorhabditis elegans nematodes harboring a loss-of-function mutation in the SWI/SNF subunit swsn-1 ( SMARCC1/2 in humans). Furthermore, we found that the combination of this specific mutation in snfc-5 and a loss-of-function mutation in either of the E3 ubiquitin ligases ubr-5 ( UBR5 in humans) or hecd-1 ( HECTD1 in humans) can restore development to adulthood in swsn-1 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 swsn-1; snfc-5 double mutants and partly restored to wild-type levels in swsn-1; snfc-5; ubr-5 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. |
