The BRCT (BRCA1 C-terminal) domain is a small, recurring protein module found in a variety of proteins across different organisms, from bacteria to humans. It is named after its discovery in the C-terminal region of the BRCA1 protein, which is linked to breast cancer susceptibility. This domain serves as a versatile building block within proteins, allowing them to participate in fundamental cellular processes.
Understanding the BRCT Domain Structure
The BRCT domain consists of 90 to 100 amino acids and adopts a characteristic fold. This structure features a central, parallel four-stranded beta-sheet, with alpha-helices packed against its faces. BRCT domains often appear in tandem repeats, meaning multiple copies are linked together within a single protein.
This structural arrangement is important for its function, as it creates a binding pocket designed to recognize and attach to phosphorylated proteins. Phosphorylation, the addition of a phosphate group, acts like a molecular switch, signaling changes within the cell. The BRCT domain’s ability to bind these phosphorylated proteins is highly specific, recognizing a motif like pSer-X-X-Phe. This selective binding allows BRCT domains to act like a “lock and key,” ensuring that proteins interact only when the appropriate signal is present, thereby relaying cellular signals.
Central Role in DNA Repair and Cell Cycle Control
BRCT domains play a key role in maintaining genome stability, primarily through their involvement in DNA repair and cell cycle control. When DNA damage occurs, proteins containing BRCT domains are among the first responders, acting as sensors that detect the damage. These domains facilitate the recruitment of other proteins to the site of DNA damage, orchestrating a cascade of events necessary for repair.
In BRCA1, the BRCT domain mediates interactions with various partners important for DNA repair. These interactions depend on the phosphorylation status of binding partners, allowing for control of the repair process. BRCA1, through its BRCT domains, plays an important part in homologous recombination, an accurate DNA repair pathway for double-strand breaks.
Beyond DNA repair, BRCT domains are also involved in cell cycle checkpoints. These checkpoints are surveillance mechanisms that ensure cells do not proceed through division if their DNA is damaged. Proteins with BRCT domains help to activate these checkpoints, temporarily halting the cell cycle to allow time for DNA repair. If the damage cannot be repaired, these pathways can trigger programmed cell death, preventing the propagation of cells with compromised genetic material.
Implications in Disease
When BRCT domains are mutated or become dysfunctional, the consequences can be serious, leading to genomic instability and an elevated risk of various diseases, particularly cancer. Mutations within the BRCT domain can disrupt its ability to recognize and bind to phosphorylated proteins, which is important to its role in DNA repair. This impaired binding means that DNA damage may not be properly detected or repaired, allowing errors to accumulate in the cell’s genetic code.
For example, many mutations in the BRCA1 gene are found within its BRCT domain. These mutations can lead to a faulty BRCA1 protein that cannot effectively participate in DNA repair pathways, increasing an individual’s susceptibility to breast and ovarian cancers. The inability to repair DNA damage can result in damaged cells continuing to divide and proliferate, contributing to tumor formation.
Understanding these defects in BRCT domain function can inform diagnostic and therapeutic approaches. Identifying specific mutations in BRCT domains can help assess an individual’s cancer risk and guide personalized treatment strategies. This knowledge also provides targets for developing new drugs that might restore their activity or exploit their weaknesses in cancer cells.