A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection
Open Access
- 19 February 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 7 (8), eabc6381
- https://doi.org/10.1126/sciadv.abc6381
Abstract
Cancer cells display high levels of DNA damage and replication stress, vulnerabilities that could be exploited by drugs targeting DNA repair proteins. Human CtIP promotes homology-mediated repair of DNA double-strand breaks (DSBs) and protects stalled replication forks from nucleolytic degradation, thus representing an attractive candidate for targeted cancer therapy. Here, we establish a peptide mimetic of the CtIP tetramerization motif that inhibits CtIP activity. The hydrocarbon-stapled peptide encompassing amino acid residues 18 to 28 of CtIP (SP18–28) stably binds to CtIP tetramers in vitro and facilitates their aggregation into higher-order structures. Efficient intracellular uptake of SP18–28 abrogates CtIP localization to damaged chromatin, impairs DSB repair, and triggers extensive fork degradation. Moreover, prolonged SP18–28 treatment causes hypersensitivity to DNA-damaging agents and selectively reduces the viability of BRCA1-mutated cancer cell lines. Together, our data provide a basis for the future development of CtIP-targeting compounds with the potential to treat patients with cancer.Funding Information
- National Institute of Environmental Health Sciences (1Z01ES102765)
- Wellcome (100401/Z/12/Z)
- Swiss National Science Foundation (31003A_176161)
- Novartis Stiftung für Medizinisch-Biologische Forschung (17C155)
- Krebsforschung Schweiz (KFS-4702-02-2019)
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