Exploring the Structural Link Between BRCA1 and Carcinogenesis

The breast cancer type 1 susceptibility gene (BRCA1), located on chromosome 17, codes for a tumor suppressor protein that functions as a caretaker gene in preserving chromosomal stability. The Olathe North MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine the structure‐function relationship between this protein, BRCA1, and breast cancer. BRCA1 functions in both checkpoint activation and double stranded DNA repair. Most of BRCA1's functions occur within the nucleus where it interacts with several other proteins to mend breaks in DNA. Over 1,800 mutations of BRCA1 have been discovered within the gene itself. Many of these mutations cause a truncated protein to be coded for, resulting in a malfunctional protein incapable of repairing damaged DNA. Another function of BRCA1 is to attach ubiquitin to other proteins, which helps to regulate processes in the body and is needed for homologous recombination. Without this type of DNA repair, cells can develop mutations leading to carcinogenesis. Other BRCA1 mutations trigger cells to grow and divide uncontrollably which can also result in carcinogenesis, specifically of breast cancer tumors. It is for this reason that BRCA1 gets the name breast cancer type 1 susceptibility protein. BRCA1 is a large phosphoprotein composed of 1,863 amino acids containing a zinc finger N‐terminal RING domain and two C‐terminals referred to as BRCT. The presence of a DNA‐binding, N‐terminal RING finger domain suggests that BRCA1 may play an undefined role in transcription regulation. RING mutations in BRCA1 have often been associated with familial carcinomas. The two BRCT regions of BRCA1 each have 90–100 amino acid sequence repeats called BRCT repeats. These repeats are typically associated with members of a protein fold family that includes many other proteins associated with DNA repair. Although the molecular basis of their effects remains largely obscure, many mutations are known to target the highly conserved C‐terminal BRCT repeats that function as a phosphoserine phosphothreonine‐binding module. It is hypothesized that if the structure of the BRCT‐BRCT interface is changed, the whole BRCT domain becomes defective. Future research and observation of the effects of other missense mutations on BRCA1 cellular function would be necessary to correlate BRCT loss of structure with BRCA1 loss of function. This would also further establish protein misfolding as a basic molecular mechanism of disease. Other research prospects include the potential of using BRCA1 mutations in order to predict treatment resistance in breast cancer, and using CRISPR gene therapies to edit mutated BRCA1 genes, therefore preventing or halting further carcinogenesis. Support or Funding Information Sponsors: Chris Elniff and L.B. Fogt Mentor: Dr. Jack Treml PhD, University of Kansas Biotechnology This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .