Learning why BRCA1 mutations lead to breast cancer

BRCA1 is a gene whose name is among the most familiar to the general public of all genes – for the unfortunate reason that mutations of BRCA1 are associated with significantly increased hereditary risk for breast cancer (as the name suggests). Strangely, however, it’s still not known exactly how mutations of BRCA1 confer this greater risk for cancer. But recent research has narrowed down the possibilities.

The protein that the gene codes for, BRCA1, is a fairly long chain of 1863 amino acids. BRCA1 is known to be involved in repair of damaged DNA. If BRCA1 is defective (due to a gene mutation), the failure to properly repair DNA (which can become damaged for many possible reasons) can lead to a cell becoming cancerous.

Previous research has identified around 1500 different mutations of BRCA1 associated with cancer risk. But most of these mutations directly affect the amino acids of only two different regions of BRCA1. Every protein has an amine group at one end of its chain and a carboxyl group at the other end. One of the two regions in which mutations lead to cancer is at the amino end and is called the “RING domain”. The other region, near the carboxyl end, is called BRCT (BRCA1 carboxyl-terminal tandem repeats).

The RING domain is known to have a role in the process that attaches a marker called ubiquitin to a protein in order to identify the protein as ready for recycling. The BRCT region is associated with the process of protein phosphorylation, which is a key element of chemical signaling within cells. What hasn’t been known is what aspects of DNA repair are disrupted by defects in one or both of these regions.

The latest research, which was done with mice, has now shown that, contrary to what’s been generally assumed, the RING domain is not directly involved with DNA repair. It turns out that most mutations that affect the RING domain result in a protein that is misfolded and therefore incapable of doing anything useful. However, in mice with point mutations affecting the RING domain that don’t distort the overall protein structure, there is no increased risk of cancer – implying that DNA repair isn’t hindered.

On the other hand, point mutations that affect the BRCT region, do increase the risk of cancer, even though the overall structure of BRCA1 is not distorted. Presumably, the effect of such mutations is to prevent BRCA1 from attaching to proteins that require phosphorylation in order to assist in the process of DNA repair.

It’s known that normally BRCT can bind to at least three different DNA repair protein complexes. There might be others, but at least this narrows considerably the types of DNA repair that might be hindered as a result of BRCA1 mutations that affect the BRCT area.

BRCA1 Further Elucidated

[M]ice with a point mutation in the BRCT domain, which impaired BRCA1’s ability to bind the phosphate group of phosphorylated proteins, did develop tumors in the mammary glands and the pancreas after the wildtype BRCA1 allele was knocked down.

“These mice develop tumors almost as rapidly as mice with null mutations in BRCA1,” Baer said, suggesting that the binding of BRCA1 to other phosphorylated proteins is critical for tumor suppression.

Indeed, proteins known to bind to BRCA1’s BRCT domains—such as Abraxas, BACH1, and CtIP—are all involved in the DNA repair process. This meshes with the prevailing view that faulty DNA repair by a mutated BRCA1 results in genomic instability, which ultimately leads to tumorigenesis.

Further reading:

BRCA1, Everything But the RING?

BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity

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