New insight into protein phosphorylation related to tumor suppressive activity with normal BRCA1 gene expression may provide new targets for intervention in cells with BRCA1 mutations, according to an article in the October 23rd issue of Science. Because BRCA1 mutations are found in roughly 50 percent of inherited breast cancers, the American team explored the molecular activity associated with BRCA1 expression during normal cell cycles.

The BRCA1 gene codes for the BRCT-domain protein. Scientists had already known that binding sites for the BRCT-domain protein are found in many partner proteins involved in regulation of the cell cycle; the current work was designed to answer the question of how partner protein binding to the BRCT-domain protein regulates the normal cycle.

The investigators showed that partner proteins must be phosphorylated to bind and activate the BRCT-domain protein. After activation, the BRCT-domain protein helps regulate vital tasks in the cell cycle including signaling of DNA damage and actual repair of DNA. When these tasks are accomplished, the BRCA1 gene can function correctly to suppress tumors. Without phosphorylation of BRCA1’s binding partners, BRCA1 cannot function to suppress tumors. This leaves cells vulnerable to the cumulative mutations that can eventually produce breast cancer.

“With this breast cancer gene, the understanding is that if this gene is mutated it may trigger additional mutations throughout your lifetime and that contributes to a lifetime risk of developing breast cancer. We wanted to understand the molecular mechanism behind this,” said Junjie Chen, Ph.D., lead author of the study. “Now that we understand one aspect of it, this allows us to go to the next level, such as how to use our understanding to target cells so we can gain control of the cell cycle to stop cancers.”

One of the focuses of ongoing research is to understand the phosphorylation-protein binding-tumor suppression activity in sufficient detail that drugs can be designed to take advantage of phosphorylation bonds and therapeutically regulate cell cycle.