Related Experiment Video

Updated: Oct 4, 2025

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
09:24

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Published on: August 12, 2015

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The CIP2A-TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer

Salomé Adam1, Silvia Emma Rossi1, Nathalie Moatti1

  • 1Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

Nature Cancer
|February 5, 2022
PubMed

Insights

Cancer cells with BRCA1/2 mutations rely on CIP2A for survival. Targeting the CIP2A-TOPBP1 complex offers a new therapeutic strategy for BRCA-mutated cancers.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • BRCA1/2-mutated cancers exhibit genome instability due to homologous recombination (HR) deficiency.
  • Understanding adaptive mechanisms in these cells is crucial for developing targeted therapies.

Purpose of the Study:

  • To identify essential genes and adaptive mechanisms in BRCA1/2-deficient cancer cells.
  • To evaluate CIP2A as a potential synthetic lethal target for BRCA-mutated tumors.

Main Methods:

  • Genome-scale CRISPR-Cas9 synthetic lethality screens were performed in isogenic BRCA1- and BRCA2-deficient cell lines.
  • CIP2A's role and its complex with TOPBP1 were investigated in mitosis and at DNA lesions.

Main Results:

  • CIP2A was identified as essential in BRCA1- and BRCA2-mutated cells.
  • The CIP2A-TOPBP1 complex, localized at DNA lesions during mitosis, prevents lethal chromosome mis-segregation in BRCA-deficient cells.
  • CIP2A deficiency did not induce replication-associated DNA lesions requiring HR.

Conclusions:

  • CIP2A is a critical factor for the survival of BRCA-deficient cancer cells.
  • Disrupting the CIP2A-TOPBP1 complex is highly detrimental to BRCA-mutated tumors.
  • CIP2A represents a promising synthetic lethal therapeutic target for BRCA1/2-mutated cancers.

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