Program in Gene Function and Expression; Program in Molecular Medicine
Animals; Antigens, CD95; DNA Methylation; Epigenesis, Genetic; *Gene Expression Regulation, Neoplastic; *Gene Silencing; *Genes, Tumor Suppressor; Mice; Models, Biological; NIH 3T3 Cells; Protein Binding; RNA Interference; Signal Transduction; ras Proteins
Cancer Biology | Cell and Developmental Biology | Genetics and Genomics
We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated by binding of ZFP354B, a sequence-specific DNA-binding protein, and culminates in recruitment of the DNA methyltransferase DNMT1. RNAi and pharmacological inhibition experiments reveal that silencing requires continuous function of RAS and its cofactors and can be rapidly reversed, which may have therapeutic implications for reactivation of silenced TSGs in RAS-positive cancers.
DNMT1, RAS, RNA interference, ZFP354B, epigenetic silencing, epistasis analysis
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© 2013 Wajapeyee et al.; Published by Cold Spring Harbor Laboratory Press.This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
DOI of Published Version
Genes Dev. 2013 Oct 15;27(20):2221-6. doi: 10.1101/gad.227413.113. Epub 2013 Oct 8. Link to article on publisher's site
Genes and development
Wajapeyee, Narendra; Malonia, Sunil K.; Palakurthy, Rajendra Kumar; and Green, Michael R., "Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors" (2013). University of Massachusetts Medical School Faculty Publications. 785.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 3.0 License