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Cancer Related BRCA-1 and BRCA-2 Mutations as Analysed by the Resonant Recognition Model

It is documented that the large number of mutations within BRCA-1 and BRCA-2 genes are related to development of breast cancer, ovarian cancer, as well as prostate cancer and pancreatic cancer. However, it is not known which mutations are the most critical for formation of these cancers. We have analysed human BRCA-1, BRCA-2 and related RAD51 protein functions and functional mutations using our previously developed Resonant Recognition Model (RRM). The RRM is capable to analyse protein biological functions/interactions, predict bioactive mutations and design de novo bioactive peptides with desired biological function. The most critical mutations for formation of cancer in human BRCA-1, BRCA-2 and RAD51 proteins have been predicted and compared with experimental results. The predicted mutations within 3D structures have been presented and discussed. Such findings can lead to development of much simpler and more relevant tests for genetic predisposition to breast, ovarian, prostate and pancreatic cancers.


Introduction
BRCA-1 is a human tumor suppressor gene [1,2] and related protein is also called by the synonym breast cancer type 1 susceptibility protein. BRCA-1 protein is responsible for repairing DNA [3]. BRCA-1 and BRCA-2 are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired. Thus, these proteins are involved in DNA repair, particularly in repair of double strand breaks [3]. If BRCA-1 or BRCA-2 is damaged by mutations, then they are not able to repair DNA properly and thus there is increased risk for breast and some other types of cancer. BRCA-1 proteins are directly involved in DNA repair, while BRCA-2 proteins are also involved in DNA repair, but through binding and assembling with RAD51 proteins [4].
Certain mutations of BRCA-1 and BRCA-2 proteins are found to lead to increased risk of breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. It is possible that these mutations are diminishing BRCA-1 and BRCA-2 ability to repair DNA and consequently induce cancer development.
Mutations related to cancer development in BRCA-1 and BRCA-2 proteins are found to be inherited and are related to the ethnicity. These mutations have been spread all along protein sequences. Within human BRCA-1 protein, cancer related mutations are mostly clustered between amino acids in ranges of: 460-555, 800-960, 1020-1220 and 1660-1840 [4].
BRCA-2 protein activity is more complex, as it involves in DNA repair through binding and assembling with RAD51 proteins. Experimentally the large number of critical mutations have been found, which are spread along the whole human BRCA-2 protein, which is extremely long protein built up of 3418 amino acids [4].
Although, there have been a large number of mutations experimentally found in human BRCA-1 and BRCA-2 proteins to be potentially related to cancer development, it is still not well known which mutations are the most critical for the formation of these cancers. If it is possible to identify these critical mutations, it would create a possibility for much simpler and more relevant genetic tests for cancer predisposition. When the RRM approach was applied to human RAD51 protein to identify amino acids mostly related to DNA repair frequency the four most significant functional mutations are found to be at positions below: 105, 132, 152 and 179.
When these amino acids are positioned in 3D structure of BRCA-2/RAD51 complex (from PDB database), as presented with proposed 'hot spots' in RAD51 (blue ribbon) highlighted with CPKs in yellow and 'hot spot' at position 1523 in BRCA-2 (red ribbon) highlighted with CPKs in green in Figure  7, it can be observed that they are clustered together around the DNA binding site. Thus, they could be critical for binding to DNA. Consequently, these amino acids could be critical for DNA repair and therefore, these mutations could be critical for cancer development. It is important to note that the RRM predicted the amino acids within BRCA-2/RAD51 complex, which could be the most critical for their DNA repair function and could lead to the cancer development.

Conclusions
Here we utilised the Resonant Recognition Model (RRM), the physico-mathematical model which can analyse protein function and functional mutations, to predict the critical mutations in human BRCA-1, BRCA-2 and RAD51 proteins. All predicted mutations are within the regions in these proteins that have been experimentally found to be critical for their DNA repair function and consequently development of cancer.
It is important to note that there are a large number of mutations, experimentally found to be related to development of cancer, but there is no evidence which is the most critical. The RRM can provide an advantage of identifying small number of the most critical mutations. These findings could lead to simpler and more relevant genetic tests of mutations related to predisposition for cancer development.