User:Navroop Gill/BRCA1

Introduction to BRCA1

The BRCA1 protein is encoded by the BRCA1 gene. BRCA1 is a human tumour suppressor gene, and its main function is to repair any DNA or destroy DNA that can no longer be repaired (Yoshida & Miki, 2005). BRCA1 and BRCA2 can sometimes be confused with one another however the two proteins are unrelated (Irminger-Finger, Ratajska and Pilyugin, 2016), but both proteins will usually be found in the cells of the breast and some other tissues in which they are completing their main function of attempting to help repair DNA that is damaged, or they are destroying cells if DNA is past the point of being repaired. Both BRCA1 and BRCA2 are both involved in the repair of chromosomal damage and have the crucial role in doing an error free repair of DNA double strand breaks (Friedenson, 2007). However, if BRCA1 or BRCA2 becomes damaged itself by BRCA mutation then the primary function of itself cannot be carried which is repairing damaged DNA and this would mean the damaged DNA will not be repaired correctly or properly. This will cause issues and increase the risk of cancer, most commonly breast cancer (Friedenson, 2007). Therefore, both BRCA1 and BRCA2 are often described as ‘breast cancer susceptibility proteins’ and/or ‘breast cancer susceptibility genes’ and this is because mutations in these proteins are a factor in an increased risk of breast cancer. Out of the two alleles, the predominant allele will have a normal function of tumour suppression however mutations of high penetrance in these genes will result in a loss of the tumour suppressive function which corresponds to a higher risk of breast cancer (O’Donovan and Livingston, 2010).

The functions of BRCA1

BRCA1 as explained above is part of a sophisticated complex that repairs double-strand breaks in DNA. The strands of the DNA double helix will break constantly and continuously as they become damaged, this can mean at time only one strand may be damaged and broken but some other times both strands could concurrently be damaged and broken. DNA cross-linking agents are a very essential source to indicate chromosomal or DNA damage. When crosslinks are removed is when double-strand breaks happen, and this triggers a biallelic (affecting both alleles of the gene) mutations in BRCA1 and this has been recognised as the reason for Fancomi Anemia (FA is a rare genetic disease that results in an impaired response to DNA damage) (D’Andrea, 2010), completion group S, a genetic disease that is interlinked to the hypersensitivity to DNA crosslinking agents (Sawyer et al., 2015). The BRCA1 protein is involved and a part of a protein complex that is responsible for repairing DNA when both the strands are broken. When this may occur, it is challenging for the repair mechanism to figure out how it may replace the DNA sequence which is correct, and which way to repair it as there are various ways the broken strands could be repaired. The double-strand repair mechanism of which BRCA1 is a part of is known as the homology-directed repair, in this is where the proteins in charge of repair will copy the identical sequence from the intact sister chromatid (Sawyer et al., 2015). Inside the nucleus of various types of normal cells, there is an interaction between the BRCA1 proteins and the Rad51 during the repair of DNA double-strand breaks (Boulton, 2006). The double-strand breaks can be the result of natural radiation or some other exposures, however, it can also happen when chromosomes exchange genetic material, the genetic material can be the homologous recombination (HR) (Boulton, 2006). Whereas the BRCA2 protein, which also has similarities in its function compared to BRCA1, also interacts with the Rad51 protein just as the BRCA1 protein does. By affecting and regulating the DNA damage repair, the three proteins (BRCA1, BRCA2, and Rad51) are responsible in playing a role to maintain the stability of the human genome (Boulton, 2006).

The structure of BRCA1

The BRCA1 protein consists of the domains listed below:

1. The RING domain (also known as Zinc ring finger domain)

2. BRCA1 C Terminus (BRCT) domain

The BRCA1 also consists of nuclear export signals (NES) and nuclear localisation signals (NLS) motifs (Henderson, 2005). A nuclear export signal (NES) is a short target peptide that consists of 4 hydrophobic residues in the protein that will target the NES for exportation out of the cell nucleus to the cytoplasm going through the nuclear pore complex via nuclear transport. Contrary to nuclear export signals, nuclear localisation signals (NLS) will target a protein which is located within the cytoplasm so that it can be imported to the nucleus. NESs perform various cellular functions that are important. One being that they assist in regulating the position of proteins within the cell, this then allows NESs to affect transcription and many other nuclear functions that are crucial to a cell functioning properly (Fukuda et al., 1997). Thus, the role of NES is to export a protein out of the nucleus whereas, the role of NLS is to import a protein to the nucleus.

The BRCA1 protein in humans contains 4 major protein domains which are the following: RING domain (Zinc finger C3HC4), the two BRCT domains and lastly the BRCA1 serine cluster domain (SCD). These four domains together encode and estimated 27% of the BRCA1 protein. As of now, there are 6 known isoforms of BRCA1 and both isoform 1 and isoform 2 consist of 1863 amino acids each.

BRCA1 mutations and increased risk of cancer

Some select types or variants of the BRCA1 will cause an increased risk of breast cancer as part of the hereditary breast-ovarian cancer (HBOC) syndrome. HBOC are cancer syndromes that will cause there to be an increase the normal levels of breast cancer, ovarian cancer, and several other cancers in genetically related families. Damaging mutations in the BRCA1 or BRCA2 can result in a very high rates of breast and ovarian cancer. The mutations in BRCA1 are linked with a 39-46% risk of ovarian cancer and on the other hand, mutations in the BRCA1 are linked to around a 10-27% risk of ovarian cancer (Ring, Garcia, Thomas and Modesitt, 2017). Females with an unusual BRCA1 gene and BRCA2 gene together have around an 80% risk of developing breast cancer by the age of 90. BRCA1 mutations can be altering of DNA base pairs (the building blocks of DNA) by one of even a small amount of DNA base pairs, these changes can be identified via PCR and DNA sequencing (Ring, Garcia, Thomas and Modesitt, 2017). Germline mutations in the BRCA1 tumour suppressor gene often result in a significant increase in susceptibility to breast and ovarian cancers.

Questions

Q1. What is the BRCA1 protein best known for?

Q2. Are the proteins BRCA1 and BRCA2 related?

Q3. Which 3 proteins are responsible for maintaining the stability of the human genome?

Q4. How many major protein domains are found within the BRCA1 protein in humans?

Q5.A mutation in BRCA1 causes an increased risk of which cancer?