BRCA1

BRCA1 gene is found to have a significant correlation with breast and ovarian cancer. It is one of the major genes found to mediate tumor suppression though interaction with different network of DNA repair proteins and chromatin. In fact, BRCA1 was found to be associated with 13 different proteins that participate in DNA repair and cancer susceptibility. A mutation in BRCA 1 gene often results in homologous recombination (HR) causing DNA repair deficiency and instability.

Statistic

BRCA1 gene is not accountable for all breast and ovarian cancer. In fact, it is only responsible for approximately 20% of hereditary breast cancer. Individuals who inherited one mutated allele do not show apparent phenotypic abnormalities but does suffer an 85% higher risk for breast cancer. BRCA1 mutated carrier also have a 30-50% higher risk of developing ovarian cancer. Approximately 80% of the breast cancer caused by mutation in BRCA1 resemble sporadic basal like triple-negative cancer, which results in exhibiting a basal histology and being negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/Neu). BRCA, however, is not responsible for only breast and ovarian cancer. Several BRCA1 associated proteins show correlation with Fanconi anemia (FA), a diseases that cause bone marrow failure, development defects, heighten sensitivity to DNA crosslinking agents and increased cancer incidents.

Structural feature

BRCAI is made out of 1863 amino acid and can be divided into a few domains. Of these domain, RING domain and Exon 11 interest researchers the most. RING domain consists of the first 150 amino acid and is most commonly present in E3 ubiquitin ligases. This region can also be found in one of BRCA protein binding partner known as BRCA1- associated RING domain protein (BARD 1) BARD1 have been found in patients with hereditary breast and ovarian cancer, indicating the interaction with BARDI is important for BRCA1 function. However, the exact relative risk for BARD mutation is still unclear.

In addition, mice with E3-ubiquitin ligase deficient BRCA 1 Ring mutant show that genomic instability and tumor forming phenotype depends on the position of the mutation. When researchers substitute E3 ubiquitin ligase with BRCA1 126A, a synthetic molecule, no sign of cancer or loss of DNA repair function are observed. However, the mice show a slight decrease in body weight and male infertility. On the other hand, when the RING domain was substituted with C61G, which block the interaction between BARD1 and the RING domain in BRCAI, embryonic lethality, DNA deficiency and cancer predisposition are observed.

60% of BRCA is part of exon 11, which is present in all vertebrates. Exon 11 contains a great unstructured region that is phosophrylated by ataxia telangienctasia mutated (ATM) kinase and check point kinase2 (Chk2) in DNA damage inducible manner. If exon 11 is deleted, impair homologous recombination and genomic instability are observed. Exon 11 mutant mice do not lose all BRCA1 function whereas BRCA1 null mice die before birth due to the complete lose of BRCAI function. Moreover, a p53 heterzygote background can rescue embryonic lethality in BRCA1 exon 11 mutant mice but not in BRCA null mice.

How does BRCA1 work

BRCAI serves as a coordinator that organizes various proteins to repair DNA sequence. BRCA1 forms proteins that perform different functions but all localize at IRIFs. During the DNA damage response, ataxia telangectasia mutated kinase (ATM) and check point kinase 2 (Chk2) become activated and phosphorylate DNA damage response mediator (DDR). BRCA1, as one of the DDR mediator, recruits different proteins to accumulate at the damaged site and repairs the DNA sequence. The four protein complexes associate with BRCA 1 are BRCA1-C, BRCA1-B, BRCA1-A, and BRCA1/PalB2/BRCA2. The function of each protein complex is listed as follow:

• BRCA1-C- end resection, ATR/Chk1 activation , homologous recombination
• BRCA1-B- s phase checkpoint, homologous recombination, ICL
• BRCA1-A k63-ub chromatin targeting, G2 checkpoint, DSB repair
• BRCA1/PalB2/ BRCA2- Rad51 strand invasion, homologous recombination

Sufficient amount of BRCA1 is crucial for an error free repair. When not enough BRCA is present at the DNA damaged site, two situations can occur. First, the replication fork collapses due incorrect NHEJ DNA repair mechanisms, forming of radical chromosome structures and commensurate cellular toxicity. Second, the end of two non homologous end might join, which result in genomic instability.

Conclusion

Today, researchers have come up with several ways to treat cancers cause by BRCAI mutation. Surgical intervention can help to reduce the cancer incidence in mutation carrier and selective treatments are offered for BRCA1 mutated tumors. The discovery of BRCA1 also leads to the finding of new genes suspected for causing cancer. These findings are crucial for a biochemical understanding of how BRCA1 interact with other proteins involve in repairing DNA sequence and the function of these DNA repair proteins.

Reference

1.Links between genome integrity and BRCA1 tumor suppression. Li ML, Greenberg RA. Trends Biochem Sci. 2012 Oct;37(10):418-24. doi: 10.1016/j.tibs.2012.06.007. Epub 2012 Jul 24. PMID: 22836122 [PubMed - in process]