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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Circular ANRIL isoforms switch from repressors to activators of p15/CDKN2B expression during RAF1 oncogene-induced

Lisa Muniz1, Sandra Lazorthes1, Maxime Delmas1

  • 1LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France.

RNA Biology
|September 1, 2020
PubMed

Insights

Circular ANRIL RNAs are newly discovered regulators of gene expression and cell fate. These molecules play a key role in senescence by controlling INK4 gene expression, switching from repressors to activators depending on the senescence inducer.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cellular Senescence

Background:

  • Long non-coding RNAs (ncRNAs) regulate gene expression and cell fate.
  • The INK4 locus encodes tumor suppressors p15INK4b, p16INK4a, and p14ARF, crucial for cell cycle arrest during senescence.
  • ANRIL, a ncRNA, typically represses INK4 genes by recruiting Polycomb proteins, preventing senescence.

Purpose of the Study:

  • To investigate the role of ANRIL and its isoforms in different oncogene-induced senescence (OIS) models.
  • To determine how ANRIL expression and function change during RAF1-induced OIS.
  • To explore the regulatory mechanisms of circular ANRIL isoforms in controlling INK4 gene expression and senescence.

Main Methods:

  • Analysis of ANRIL expression and stability in various OIS models (RAF1, MEK1, BRAF).
  • Identification and characterization of circular ANRIL isoforms.
  • Investigation of circular ANRIL interactions with Polycomb proteins and their effect on gene promoters (p15, p16).

Main Results:

  • ANRIL expression increases in RAF1 OIS due to enhanced stability.
  • Two circular ANRIL isoforms are upregulated in multiple OIS models.
  • In proliferative cells, circular ANRIL represses p15; in RAF1 OIS, it promotes p15, p16, and p14 expression.
  • Circular ANRIL interacts with Polycomb proteins, decreasing EZH2 and H3K27me3 at target promoters.

Conclusions:

  • Circular ANRIL isoforms act as key regulators of INK4 gene expression during senescence.
  • The function of circular ANRIL switches from repressor to activator depending on the senescence inducer and Polycomb protein ratio.
  • These findings highlight the dynamic regulation of ANRIL and the critical role of circular isoforms in senescence pathways.
Keywords:
INK4 locusNon-coding RNAsPolycomb proteinscircular RNAsgene expression regulationoncogene-induced senescence

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