HRAD51 Involvement in Genomic Instability and Development of Breast Cancer

During the second year of the funded period, we focused on the characterization of interactions between hRAD5l and the five hRAD5l paralogs as well as interactions between these proteins and BRCA2, the BRCAl-interacting protein BARD1 and RPA. We detected strong interactions suggesting a stable complex, and weaker interactions. Some of these weaker interaction signals between hRAD5l paralogs increased in the presence of ATP and decreased in the presence of ADP which may indicate a regulatory role for adenosine nucleotides. Examination of the functional significance of these interactions is currently in progress. We have also examined the role of hRAD51-dependent DNA repair by homologous recombination in BCR/ABL-expressing cells. We found that the oncogenic tyrosine kinase BCR/ABL upregulates hRAD5l and several hRAD5l paralogs. Elevated DNA repair by recombination seems to be a major pathway by which BCR/ABL-expressing cells become drug resistant. These findings may have significant implications for cancer therapy (see accompanying reprint Slupianek at al., Mol.Cell 8, 2001).
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