The Development of Stapled Peptides that Modulate the BRCA2-RAD51 Interaction



April 29, 2013

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  • The interaction between the human recombinase RAD51 and the hub protein BRCA2 is crucial for the repair of double strand breaks via homologous DNA recombination (HDR), a key cellular pathway involved in the resistance of cancer cells to ionizing radiation and radio-mimetic drugs. BRCA2 protein binding to RAD51 is primarily mediated by a series of BRC peptide repeats that expand from the oligomerization site to the so-called Velcro site of RAD51. As revealed by recent structural and mechanistic studies, two highly conserved tetrameric aminoacid sequences FxxA and LFDE are necessary for binding. While it is understood that the FxxA sequence in the BRC repeats blocks RAD51 oligomerization by mimicking the self-association motif of RAD51, the role of the LFDE motif and the significance of its interaction with the corresponding Velcro site on RAD51 has yet to be clarified in the context of the intricate HDR process. We designed, synthetized and characterized a series of all-carbon stapled peptides based on the sequence of the BRC-4 Velcro-site binding peptide in an effort to develop inhibitors of BRCA2-RAD51 interaction. These novel stapled peptide inhibitors that modulate Rad51-BRCA2 complex formation served as chemical tools to probe the mechanism that regulates this interaction and its role in HDR.

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