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A short BRCA2-derived cell-penetrating peptide targets RAD51 function and confers hypersensitivity towards PARP inhibition


Trenner, Anika; Godau, Julia; Sartori, Alessandro A (2018). A short BRCA2-derived cell-penetrating peptide targets RAD51 function and confers hypersensitivity towards PARP inhibition. Molecular Cancer Therapeutics, 17(7):1392-1404.

Abstract

Under conditions of genotoxic stress, cancer cells strongly rely on efficient DNA repair to survive and proliferate. The human BRCA2 tumor suppressor protein is indispensable for the repair of DNA double-strand breaks by homologous recombination (HR) by virtue of its ability to promote RAD51 loading onto single-stranded DNA. Therefore, blocking the interaction between BRCA2 and RAD51 could significantly improve the efficacy of conventional anti-cancer therapies. However, targeting protein-protein interaction (PPI) interfaces has proven challenging because flat and large PPI surfaces generally do not support binding of small molecule inhibitors. In contrast, peptides are more potent for targeting PPIs but are otherwise difficult to deliver into cells. Here, we report that a synthetic 16-mer peptide derived from the BRC4 repeat motif of BRCA2 is capable of blocking RAD51 binding to BRCA2. Efficient non-cytotoxic cellular uptake of a nona-arginine (R9)-conjugated version of the BRC4 peptide interferes with DNA damage-induced RAD51 foci formation and HR. Moreover, transduction of the BRC4 peptide impairs replication fork protective function of BRCA2 and triggers MRE11-dependent degradation of nascent DNA in response to DNA replication stress. Finally, the BRC4 cell-penetrating peptide (CPP) confers selective hypersensitivity to PARP inhibition in cancer cells but spares non-cancerous cells. Taken together, our data highlight an innovative approach to develop novel peptide-based DNA repair inhibitors and establish BRCA2-derived CPPs as promising anti-cancer agents.

Abstract

Under conditions of genotoxic stress, cancer cells strongly rely on efficient DNA repair to survive and proliferate. The human BRCA2 tumor suppressor protein is indispensable for the repair of DNA double-strand breaks by homologous recombination (HR) by virtue of its ability to promote RAD51 loading onto single-stranded DNA. Therefore, blocking the interaction between BRCA2 and RAD51 could significantly improve the efficacy of conventional anti-cancer therapies. However, targeting protein-protein interaction (PPI) interfaces has proven challenging because flat and large PPI surfaces generally do not support binding of small molecule inhibitors. In contrast, peptides are more potent for targeting PPIs but are otherwise difficult to deliver into cells. Here, we report that a synthetic 16-mer peptide derived from the BRC4 repeat motif of BRCA2 is capable of blocking RAD51 binding to BRCA2. Efficient non-cytotoxic cellular uptake of a nona-arginine (R9)-conjugated version of the BRC4 peptide interferes with DNA damage-induced RAD51 foci formation and HR. Moreover, transduction of the BRC4 peptide impairs replication fork protective function of BRCA2 and triggers MRE11-dependent degradation of nascent DNA in response to DNA replication stress. Finally, the BRC4 cell-penetrating peptide (CPP) confers selective hypersensitivity to PARP inhibition in cancer cells but spares non-cancerous cells. Taken together, our data highlight an innovative approach to develop novel peptide-based DNA repair inhibitors and establish BRCA2-derived CPPs as promising anti-cancer agents.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Cancer Research, Oncology
Language:English
Date:13 April 2018
Deposited On:24 May 2018 09:37
Last Modified:19 Aug 2018 15:46
Publisher:American Association for Cancer Research
ISSN:1535-7163
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/1535-7163.MCT-17-1156
PubMed ID:29654063
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_156023
  • : Project TitleMechanisitic insights into the regulation of DNA double-strand break repair
  • : FunderSNSF
  • : Grant ID31003A_176161
  • : Project TitleKeeping DNA repair nucleases in check to maintain genome stability

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