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A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and

Anika Kuster1, Nour L Mozaffari1, Oliver J Wilkinson2

  • 1Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Science Advances
|February 20, 2021
PubMed

Insights

Researchers developed a peptide inhibitor (SP18-28) targeting CtIP, a DNA repair protein. This peptide disrupts DNA repair and selectively kills BRCA1-mutated cancer cells, offering a potential new cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • Cancer cells exhibit high DNA damage and replication stress.
  • DNA repair proteins like CtIP are potential therapeutic targets.
  • CtIP is crucial for DNA double-strand break repair and replication fork stability.

Purpose of the Study:

  • To develop a peptide mimetic inhibiting CtIP activity.
  • To investigate the therapeutic potential of targeting CtIP in cancer.

Main Methods:

  • Creation of a hydrocarbon-stapled peptide (SP18-28) mimicking the CtIP tetramerization motif.
  • In vitro binding assays and assessment of CtIP tetramer aggregation.
  • Evaluation of intracellular uptake, chromatin localization, DNA repair, and replication fork stability.
  • Testing sensitivity to DNA-damaging agents and cancer cell viability assays, including BRCA1-mutated lines.

Main Results:

  • SP18-28 binds CtIP tetramers and induces aggregation.
  • SP18-28 treatment impairs CtIP's role in DNA repair and causes replication fork degradation.
  • SP18-28 treatment increases sensitivity to DNA-damaging agents.
  • SP18-28 selectively reduces viability in BRCA1-mutated cancer cells.

Conclusions:

  • SP18-28 effectively inhibits CtIP function in cancer cells.
  • Targeting CtIP with peptide mimetics shows promise for cancer therapy.
  • This approach may be particularly effective for BRCA1-mutated cancers.

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