Inhibitors of XRCC3p
Abstract
DNA repair via the homologous recombination (HR) pathway requires the recombinase RAD51 and, in vertabrates, five RAD51 paralogs. The paralogs form two complexes in solution, a XRCC3/RAD51C heterodimer and a RAD51B/RAD51C/RAD51/XRCC2 heterotetramer. Mutation of any one of the five paralogue genes prevents subnuclear assembly of recombinase at damaged sites and renders cells 30-100 fold sensitive to DNA cross-linking drugs. Here we used phage display to isolate peptides that bind the paralog XRCC3. Sequences of binding peptides showed similarity to residues 14-25 of RAD51C protein. Point mutations in this region of RAD51C altered its interaction with both XRCC3 and RAD51B in a two-hybrid system. A synthetic peptide composed of residues 14-25 of RAD51C fused to a membrane transduction sequence (PTD4) inhibited subnuclear assembly of RAD51 recombinase and sensitized Chinese hamster ovary (CHO) cells to cisplatin when added to growth medium. These results suggest that residues 14-25 of RAD51C contribute to a hot spot' utilized in both xRCC3-RAD51C and RAD51B-RAD51C interactions. Peptide-based inhibition of HR may prove useful for improving the efficacy of existing cancer therapies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2003
- Accession Number
- ADA423036
Entities
People
- Douglas K. Bishop
- P. P. Connell
Organizations
- University of Chicago