Daniel Haber (Massachusetts General Hospital and Cancer Centre, Boston) and Jeff Parvin (Brigham and Women's Hospital and Harvard Medical School, Boston) presented evidence for a role of BRCA1 in transcriptional regulation. New technology in the form of high-density oligonucleotide arrays was exploited to identify BRCA1 target genes and Haber suggested a possible role for Gadd45 expression in BRCA1-induced apoptosis. However, Heinz Ruffner (Salk Institute, San Diego) did not observe a similar induction of Gadd45 following doxycycline-induced BRCA1 expression and the answer to this question remains to be resolved. Ruffner also presented new data on the nuclear localisation signals present in BRCA2, showing that the first of the three nuclear localisation signals at the carboxyl-terminus was sufficient to localise BRCA2 to the nucleus. This is relevant because most of the disease-causing mutations occur amino-terminal of this nuclear localisation signal, providing a neat explanation for loss of function since the mutant protein would be cytoplasmically localised. However, this would fail to adequately explain the differences in phenotype observed in the mouse models described to date [1,2,3,4]. Jeff Parvin insisted that size does matter, presenting evidence that during S-phase of the cell cycle BRCA1 exists in different-sized multiprotein complexes which make up the transcriptional machinery of the cell.
BRCA2 has been reported to interact with a number of proteins and Nicola Marston [Institute of Cancer Research (ICR), London] and Luke Hughes-Davies (CRC/Well-come, Cambridge) described some of the more recently discovered partners. DSS1, DNA methyltransferase1, andEMSY were discovered using yeast two-hybrid analysis. This implicated possible involvement of BRCA2 in cell cycle completion, methylation status of freshly replicated DNA in response to DNA damage, and in transcriptional regulation, respectively.
Paul Freemont [Imperial Cancer Research Fund (ICRF), London] concluded the meeting with a splendid demonstration of 3D computer modelling of the BRCA1 BRCT domains and demonstrated how two BRCT domains might interact. Intriguingly, disease-causing mutations that occur at high frequency, as reported in the Breast Information Core (BIC) database (http://www.nhgri.nih.gov/Intra-mural_research/Lab_transfer/Bic/index.html), tend to occur at residue locations that are probably involved in the interaction of two BRCT domains.