Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors (original) (raw)

  1. Sunil K. Malonia2,3,4,5,
  2. Rajendra K. Palakurthy2,3,4 and
  3. Michael R. Green2,3,4,6
  4. 1Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
  5. 2Howard Hughes Medical Institute,
  6. 3Program in Gene Function and Expression,
  7. 4Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
  8. ↵5 These authors contributed equally to this work.

Abstract

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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