Protein BRCA1 keeps neuroblastoma stable

Protein BRCA1 keeps neuroblastoma stable

Anyone who has ever studied the molecular basis of breast cancer will probably have heard of the abbreviation BRCA1 - this is a protein that protects the cells of breast tissue against cancer. Surprisingly, this protein can also have an opposite effect: In another type of cancer, neuroblastoma, it helps to keep the tumor stable.

Neuroblastoma is a cancer that occurs in early childhood. Degenerate cells of the nervous system grow into tumors in the abdominal cavity; the disease can progress very differently. Less aggressive tumors can be treated well or disappear spontaneously. On the other hand, the survival prospects for children whose cancer cells contain the tumor protein MYCN are particularly poor.

"In aggressive neuroblastomas, the tumor protein MYCN must interact with BRCA1 in order to keep the tumor alive," says the senior author. The group discovered this in cell culture experiments. The results were also confirmed in tissue material from patients: Tumors of children, which contain MYCN, always have high concentrations of BRCA1.

In a publication in Nature, the team describes the mechanism by which the BRCA1 protein keeps neuroblastoma cells alive. Because cancer cells grow far too fast and divide far too often, they have to run their metabolism at very high speed. This means stress for the cells, and this is where BRCA1 comes in: "Put simply, it ensures that the cells are able to cope with this stress," explains  the lead author.

More precisely: In the cells of the neuroblastoma, now the protein MYCN controls transcription, i.e. the reading of genetic information in the cell nucleus. The senior author compares this process, which is essential for the survival of the cell, with a train running on a track. "If the track is damaged, the train comes to a standstill. The growth of the tumor cell stops, it threatens to die." In this case, the protein BRCA1 ensures that a switch to a side track is opened. There, the train can wait until the tumor cell has repaired the damage on the main track.

Authors show that, similar to MYC, activation of MYCN in human neuroblastoma cells induces escape of RNAPII from promoters. If the release of RNAPII from transcriptional pause sites (pause release) fails, MYCN recruits BRCA1 to promoter-proximal regions. Recruitment of BRCA1 prevents MYCN-dependent accumulation of stalled RNAPII and enhances transcriptional activation by MYCN.

Mechanistically, BRCA1 stabilizes mRNA decapping complexes and enables MYCN to suppress R-loop formation in promoter-proximal regions. Recruitment of BRCA1 requires the ubiquitin-specific protease USP11, which binds specifically to MYCN when MYCN is dephosphorylated at Thr58. USP11, BRCA1 and MYCN stabilize each other on chromatin, preventing proteasomal turnover of MYCN. Because BRCA1 is highly expressed in neuronal progenitor cells during early development and MYC is less efficient than MYCN in recruiting BRCA1.

So the proteins MYCN and BRCA1 work hand in hand to ensure that the metabolism of tumor cells can continue to run at full speed. The team became aware of this when they looked for previously unknown targets in neuroblastoma cells that could be used to inhibit tumor growth.

Although patients with neuroblastoma will not benefit immediately from the new findings, the team will pursue the topic. They expect that the findings will contribute to the development of new therapies for this disease. They also hope to clarify whether MYCN and BRCA1 proteins only work together in neuroblastomas or whether there is a general mechanism that also affects other types of cancer.