The multifunctional nature of BRCA1 has led many to believe that it regulates processes such as transcription and DNA repair by a common mechanism. Now, Rong Li and colleagues, reporting in the 10 December issue of The Journal of Cell Biology, provide evidence indicating that this mechanism is chromatin unfolding, and that it is altered by many cancer-predisposing BRCA1 mutations.

To investigate the effect of BRCA1 on chromatin structure, the authors used a cell line containing many copies of the lac operator, which forms a large heterochromatic region. Immunofluoresence using antibodies against the lac repressor — which binds to the lac operator sequences — allows the region to be visualized as a compact nuclear dot. Expression of a BRCA1–lac repressor fusion protein alters this structure in 14% of cells: it becomes irregularly shaped, indicative of chromatin unfolding. The authors used deletion analysis to identify three regions of BRCA1 that could induce this unfolding in BRCA1's carboxy-terminal transcriptional activation domain. They include activation domain 1 (AD1), and the two BRCA1 C terminus repeats (BRCT1 and BRCT2), which lie within AD2.

Histone modification is a known chromatin-regulation mechanism, so is this involved in BRCA1-mediated regulation? Unlike p53 and E2F1 — two other transcription factors that induce chromatin unfolding — BRCA1 does not induce hyperacetylation of histones H3 and H4. It does, however, induce phosphorylation of H2AX, a variant of histone H2A, although this has not been directly linked to chromatin regulation.

So how is this chromatin regulation related to cancer-predisposing BRCA1 mutations? When classified according to their effect on chromatin unfolding, BRCA1 mutations fall into three classes, two of which have an effect on chromatin regulation. Nonsense mutations result in C-terminal truncations that are defective in transcription and repair, and do not show chromatin unfolding, and mutations within AD2 result in an enlargement of the unfolded chromatin structure and an increase in the number of cells with unfolded chromatin.

What remains to be determined is whether the BRCA1 mutation classes that cause different effects on chromatin unfolding also lead to different effects on risk, types or prognosis of BRCA1-associated cancers.