A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33608267.
- Also identified by DOI 10.1126/sciadv.abc6381 and PMC identifier 7895427.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 (SP<sup>18-28</sup>) stably binds to CtIP tetramers in vitro and facilitates their aggregation into higher-order structures. Efficient intracellular uptake of SP<sup>18-28</sup> abrogates CtIP localization to damaged chromatin, impairs DSB repair, and triggers extensive fork degradation. Moreover, prolonged SP<sup>18-28</sup> treatment causes hypersensitivity to DNA-damaging agents and selectively reduces the viability of <i>BRCA1</i>-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.