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Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors

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 b...

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Autores principales: Wajapeyee, Narendra, Malonia, Sunil K., Palakurthy, Rajendra K., Green, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814642/
https://www.ncbi.nlm.nih.gov/pubmed/24105743
http://dx.doi.org/10.1101/gad.227413.113
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author Wajapeyee, Narendra
Malonia, Sunil K.
Palakurthy, Rajendra K.
Green, Michael R.
author_facet Wajapeyee, Narendra
Malonia, Sunil K.
Palakurthy, Rajendra K.
Green, Michael R.
author_sort Wajapeyee, Narendra
collection PubMed
description 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.
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spelling pubmed-38146422014-04-15 Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors Wajapeyee, Narendra Malonia, Sunil K. Palakurthy, Rajendra K. Green, Michael R. Genes Dev Research Communication 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. Cold Spring Harbor Laboratory Press 2013-10-15 /pmc/articles/PMC3814642/ /pubmed/24105743 http://dx.doi.org/10.1101/gad.227413.113 Text en © 2013 Wajapeyee et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/3.0/ 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/.
spellingShingle Research Communication
Wajapeyee, Narendra
Malonia, Sunil K.
Palakurthy, Rajendra K.
Green, Michael R.
Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors
title Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors
title_full Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors
title_fullStr Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors
title_full_unstemmed Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors
title_short Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors
title_sort oncogenic ras directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors
topic Research Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814642/
https://www.ncbi.nlm.nih.gov/pubmed/24105743
http://dx.doi.org/10.1101/gad.227413.113
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