BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Interest in BRCA1 stems from its role as a tumour suppressor in breast and ovarian cancer. Intensive research in BRCA1 has revealed little about its specific role in cancer; rather, this protein has been implicated in a multitude of important cellular processes.
The diverse biochemical activities of BRCA1 combine to protect the genome from damage.
New data reveal that BRCA1
- transcriptionally regulates some DNA-repair genes, and, in addition,
- new roles for BRCA1 have been identified in heterochromatin formation on the X chromosome,
- doublestrand break repair, and
- ubiquitination.
BRCA1 functions in several processes, but it is unclear how these relate to the BRCA1 requirement in all cell types. Similar to the p53 tumour suppressor, BRCA1 activates genes encoding the DNA-repair response. Unlike p53, BRCA1 also has a direct role in the repair process.
According to the earlier suggested model, BRCA1–BARD1 functions in genome surveillance by scanning active genes in association with the holo-pol, and when the elongating transcription complex encounters DNA lesions, BRCA1 initiates a repair response. It is interesting to note that a BRCA1-binding cofactor, COBRA1, which regulates BRCA1 function in a chromatin decompression assay, has been found to be a required subunit of a complex that regulates transcription elongation.
When damage is encountered on the DNA template, the lesion could be corrected by transcription-coupled repair (step 1), a known BRCA1 function. Alternatively, some types of damage might require that the polymerase be removed to effect repair. Since the polymerase synthesizing mRNA on a DNA template is quite stably bound, it has been hypothesized that BRCA1 would then ubiquitinate the polymerase signaling its degradation (step 2).
Although current evidence does not implicate BRCA1 in this process, the polymerase is ubiquitinated and degraded following DNA damage. The residual BRCA1 complex might remain bound to the DNA lesion.
BRCA1 has been found to bind DNA cruciforms and three-way junctions, such as might occur at damage sites (step 3). This bound BRCA1 would then recruit repair factors, such as the RAD50-containing complex, which would then mend the lesion (steps 4 and 5).
One might infer from the recruitment of the H2AX kinase to sites in which BRCA1 is bound to DNA that this surveillance of the template by transcription results in BRCA1-dependent degradation of the transcription apparatus and recruitment of the H2AX kinase to nucleate the assembly of a repair focus.
Although there is no yeast homolog for BRCA1, perhaps a analogous pathway is conserved in this organism, mediated by a transcription elongation factor that is genetically linked in this pathway to holo-pol components.
The key cellular functions assigned to BRCA1 are numerous. BRCA1 can interact with many cellular proteins and pathways, but how these many interactions address the key questions of required ubiquitous function and tumour suppressing breast and ovarian cell function are unclear. These diverse activities of BRCA1 may be linked in a single pathway, or BRCA1 might function in multiple nuclear processes.
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Dr. Saha, good post. There is a very interesting therapeutic strategy now concerning the BRCA1/2 mutant patient. It has been shown that PARP inhibitors are extremely effective in BRCA1/2 patients as there can still be NHEJ repair (nonhomogous recombination repair) which the PARP inhibitor will take care of. This was discovered because PARP inhibitors are not that effective in BRCA1/2 wild type patients. This might be a great post. Look up University of Pennsylvania which is doing a tril on this in breast/ovarian. Also a friend of mine at Kansas, Dr. Thuy Vy Do in the lab of Dr. Andy Godwin is doing similar research. I certainly could talk to them for you and set up a connection if you’d like.
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