Phosphorylation Needed for BRCA1 Protein to Suppress Tumors

Researchers have traced the role of phosphorylation in the functioning of a protein-domain module that is found in many proteins that participate in DNA-damage checkpoint or DNA-repair pathways. The importance of this protein is underlined by the fact that an estimated 50% of inherited breast cancers are linked to mutations in the gene that encodes it.

The carboxyl-terminal domain (BRCT) of the breast cancer gene BRCA1 protein is an evolutionarily conserved module that exists in a large number of proteins from prokaryotes to eukaryotes. Investigators at the Mayo Clinic (Rochester, MN, USA) reported in the October 24, 2003, issue of Science that the BRCA1 BRCT domain interacted directly with phosphorylated BRCA1-associated carboxyl-terminal helicase (BACH1).

This specific interaction between BRCA1 and phosphorylated BACH1 was cell-cycle regulated and was required for DNA damage–induced checkpoint control during the transition from G2 to M phase of the cell cycle. Two other BRCT domains interacted with their respective physiologic partners in a phosphorylation-dependent manner, while 13 additional BRCT domains also preferentially bound phospho-peptides rather than non-phosphorylated control peptides.

"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,” explained senior author Dr. Junjie Chen, a researcher in the department of oncology at the Mayo Clinic. "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.”




Related Links:
Mayo Clinic