An unfolding breast cancer story

BRCA1 is one of the most intensely studied proteins in the history of cancer research, and it has more than its fair share of proposed protein partners and postulated activities. Rong Li hopes that he has made sense out of this mountain of information in a paper by Ye et al. starting on page 911. He and his coauthors suggest that BRCA1's effects on transcription and DNA repair have as their root cause a chromatin-unfolding activity of two BRCT repeats at the COOH terminus of the protein.

The assay for unfolding used here has been used with transcriptional activators. It involves targeting BRCA1 or a subset of the protein to multiple (probably several thousand) lacO repeats scattered over 90 Mb of heterochromatin. In 14% of cells expressing BRCA1 linked to the lac repressor there is decondensation of this focused spot of DNA. Either BRCT1 or BRCT2 alone cause an even greater extent of decondensation in a higher percentage of cells (60%), although a construct containing both BRCT repeats has no effect. This suggests that the intact protein may be inhibited for chromatin unfolding, either by the binding of another protein or because of an intramolecular interaction that is relieved by another protein.

A candidate for that other factor is COBRA1, which Ye et al. isolate as a protein that interacts with BRCT1. COBRA1 by itself can mediate chromosome decondensation. A subset of cancer-causing BRCA1 mutations that result in greater unfolding activity also show greater COBRA1 binding activity, although Ye et al. do not yet know whether such mutations have dominant effects either in cells or people.

Chromatin unfolding could change both transcription and DNA repair by increasing DNA accessibility and helping to recruit other factors. Additional recruitment activities of BRCA1 still seem to be important, as BRCT1 by itself can cause unfolding but not transcription enhancement. ▪