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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in

Li Xie1, Claude Gazin, Sung Mi Park

  • 1Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Plos Genetics
|January 4, 2013
PubMed

Insights

Cancer cells lacking p53 show a dependency on ETV1 and ATR. Inhibiting these, or TERT, halts cancer growth, revealing a new therapeutic target for p53-deficient cancers.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer cells develop dependencies on specific genes and pathways due to genetic and epigenetic changes.
  • These dependencies represent potential therapeutic vulnerabilities.
  • The tumor suppressor protein p53 plays a critical role in preventing cancer development.

Purpose of the Study:

  • To identify genes essential for the proliferation of p53-deficient (p53-) human cancer cells using an RNA interference (RNAi) screen.
  • To uncover potential therapeutic targets specific to p53-deficient cancers.

Main Methods:

  • Conducted an RNA interference (RNAi)-based synthetic interaction screen.
  • Compared gene requirements between p53-deficient and p53-competent cancer cell lines.
  • Utilized gene knockdown, gene expression analysis, and chromatin immunoprecipitation.

Main Results:

  • p53-deficient cancer cells are preferentially sensitive to the loss of transcription factor ETV1 and DNA damage kinase ATR.
  • Knockdown of ETV1 or ATR in p53-deficient cells reduces telomerase catalytic subunit (TERT) expression, causing growth arrest.
  • ETV1 binds downstream of the TERT transcriptional start site in p53-deficient cells.
  • ATR phosphorylates and stabilizes ETV1.

Conclusions:

  • A regulatory pathway involving ETV1, ATR, and TERT is crucial for the proliferation of diverse p53-deficient cancer cells.
  • This pathway represents a potential therapeutic vulnerability in p53-deficient cancers.
  • Targeting ETV1, ATR, or TERT could offer a strategy for treating p53-deficient cancers.

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