Brca Genes And Human Cancer Biology Essay

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Our human cell organisation has made evolution of unusual diversity of many frame designs. Many of this design can be traced back to the basic building blocks of tissue which composed of amino acids and endowed with autonomy and adaptation. These cell carries complete genomes sequences which not even required by itself and they are able to grow rapidly and divided after completion of organismic development. The morphogenesis of cell makes it is possible to maintain the structure of the individual cell and tissue throughout its life span. This involved repair mechanism that will maintain the cell at its original structure and function, but what happen when this cell poses a danger such as alteration in genome sequence and structure or mutation occurs? This mutated cell then will be switch into a different cell that will function abnormally and alter the cellular growth and lead to larger cell that does not obey the rules to make the normal tissue and function. This will results a tumour which is a cell that undergo abnormal cell growth. Tumours rise from normal tissue and can be identified as benign and malignant. The begin tumour does not invade adjacent tissue while the malignant invade the adjacent tissue and spawned metastases. The majority of the tumours in human are benign and harmless but there are some uncommon cases where expansion of these localized masses causes them to press on vital organs and tissue. Epithelial tissue has been identified as the major location of tumour arisen. They caused the most common human cancers which is carcinomas. These tumours cause more than 80% of cancer related death in the world.

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One of the most common genes that will play in our mind is BRCA1 and BRCA2 which is related to breast and ovarian carcinomas. Most identified breast cancer are said to be a germ line transmission of BRCA1 and BRCA2 mutant. Initially they were thought as part of the tumour suppressor gene which regulates the dynamics of cell proliferation, survival, and differentiation but rapid research shows that these genes are completely different than the others as they involved in maintenance of genomic integrity. BRCA1 and BRCA2 usually found to be participating with other proteins in the cell such as RAD50/MRE11 and RAD51 which plays vital role in repairing DNA breaks caused by radiation particles along with certain mismatch proteins. More research had been carried out regarding these BRCA genes to show that that actually play more role than just DNA break repair and homologous recombination only.

Nearly 5% of human associated with breast cancer are due to mutation of BRCA1 and BRCA2 which has been well studied in ovarian cancer and breast cancer. BRCA is belong to family RNF ring type zinc fingers and located at 17q21 in the chromosome. These genes are important in cellular development and deletion of them because embryonic lethality in mice (Sharan et al Nature 1997, 386:804-810) studies also reveal that the genes also required for maintenance of genome integrity and for normal levels of resistance to DNA damage. If these BRCA gene is inefficient in repairing the DNA damage by homologous, the cell are subjected to apoptosis (Connor et al Nature Genet 1997, 17:423-430).

The BRCA 1 is about 208kDa and BRCA2 is about 384 kDa and they function mutually as multipart that perform directly in double strand break repair. Initial experiment in mice shows defective cell lines of BRCA1 and BRCA2 and knockout shows similar response to DNA damaging agents. Then the BRCA1 and BRCA2 defective sell lines shows fault in DSB repair by homologous recombination. Also these two genes appear to co occurrence to DNA damage induced nuclear foci. Only a small amount of BRCA1 is found in organization with BRCA2 even though they both are able to interact each other. They both seem to involved in different protein complexes and play role in DSB repair. BRCA 1 has been proved to be part of BASC which contains amino acid that is crucial for DNA repair mechanism which also involved the MRE11, RAD5, NB51 repair complex. It also interacts with RNA polymerase 11 holoenzyme , ATR(cell -cycle checkpoint kinase) FANCD2 (Fanconi's anaemia protein) but this need further investigation. Whereas BRCA2 seems more restricted and only interact with RAD51 a homologous recombination repair protein.RAD51 bind single stranded DNA molecules which will cause them to invade and then unwind the double strand helices . This process is important in initiating homologous direct repair mechanism. There is an important observation about BRCA 2 gene , it has 8 BRC domains binding RAD51 molecules showing that this gene play role in assembling strings of RAD51 so that it will be single stranded DNA(ssDNA). Research also shows that RAD51not able to involve in the sites of double stranded DNA breaks in absence of BRCA1 and brca2 and some steps in homologous repair not happen properly. Lieber et al made a conclusion after a research on patient suffering from Nijmegen break syndrome that this homology directed repair is defective in them as their cell lack the NBS1 protein which not successfully performs the initial stage of homologous directed repair. This lacking causes the cells to fuse two dsdna via the process nonhomologous end joining(NHEJ) which is a error prone process because the difference in alignment between the wild type sister chromatid. This process occurs extensively in G1 phase of cell cycle and plays role in normal DNA repair processes.

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The 3' end of the brca1 contains two BRCT motifs which are important for protein interaction but in caner mutated gene that has connection with brca1 this carboxyl region also missing showing there might be a role in brca1. Recent identification of 130 kDa polypeptide which interacts with BRCA 1 which has similar motifs to BRCT,and the analysis of the sequences shows that it has nature of the DEAH helicase family which is called BACH1(BRCA1 -associated carboxyl-terminal helicase). The involvement of BRCA1 with BACH1 has been experimentally investigated and it was shown that BRCA1 is essential for formation of nuclear focus by BACH1 and this further shows it plays role in cellular localization regulation. This BRCA1 can be involved in transcription, replication and DNA repair mechanism and consequently the BACH1 can involve in this process as well. Cantor et al demonstrate that the over expression of this BACH1 gene which carried a mutated lysine residue decrease the power of the cell to repair the double stranded breaks.. Besides that mutated BACH1 have been identified in 30% of women's with initial breast cancer.1% of mutation analysed to be highly conserved in ATP binding domain and cause the decline in BACH1 protein and will cause lose in function.

BARDI is another protein that interacts with BRCA1 . It contains a conserved RING finger motif, linked to ubiquitination. When BARDI binds to RING finger motif, it poses a ubiquitin ligase activity.(Wu lc et al Nat gene 1996, Zhang XD et al, Embo jouna1998) interestingly a mutation in BRCA1 associated with RING finger shows that the ubiquitin activity destroyed. They show that several mutation in this gene will cause increase sensitivity to DNA damaging agents. Distinct complexes formed by BRCA1 and BRCA2 are involved in a variety of cellular processes such as damage signalling, protein degradation and both direct and indirect effects on the mechanisms of homologous recombination and DNA repair. Defects in these processes can lead to inefficient repair of DNA damage, genomic instability and tumourigenesis. Liu and West Breast Cancer Res 2002 4:9

The question now arisen how this combination of BRCA1/BACH1 and BRCA2/RAD51 play vital role in double strand repair?

We need to understand this BRCA1 interacts with a lot of different proteins and is more like have multiple functions. Few of its function have been exploited earlier. Several protein that interacts with BRCA1 such as BACH1,BLM,MRE11,RAD50 have exhibit helicase/nuclease activities. So it is likely that BRCA1 may help to aim this proteins to DSBs where they involve in break division. Or this protein that interacts with BRCA1 may be engage in dispensation of recombination transitional that enclose Holliday junctions. This is proved by the observation of BRCA1 that binds DNA and inhibits the exonuclase activities of MRE11/RAD50/NBS1 complex and most shows that it's more prefer a branched DNA structure(Garcia-higuera et al mol cell2001). After the repair process is completed the ubiquitin ligase activity of BRCA1/BACH1/BARDI might play role for down regulating the proteins participate in cell cycle progression during early steps of DNA repair.

Interactions of BRCA1 and BRCA2 with other proteins, or protein complexes. As determined by two-hybrid screens, co-immunoprecipitation analyses and co-fractionation studies. In general, the protein-protein associations of BRCA1 have been shown to be distinct from those exhibited by BRCA2 .Liu and West Breast Cancer Res 2002 4:9

These function of the the BRCA1 and BRCA2 has been widely exploited in recent years to develop new drugs to treat breast cancer. The concept is not an easy concept as it required a long time to get sample. The enzyme poly (adenosine disphosphate(ADP) ribose) polymerase (PARPs) is part of large multifunctional enzymes. One of the richest one is PARP1 which involved in repairing the SSDB via base excisions repair. When this PARPs inhibited, it leads to build up of DNA single strand breaks at the end of replication fork. Usually error prone mechanism will repair this breaks which involved the BRCA1 and BRCA2. When mutation happens in BRCA genes it causes genetic abnormality which leads to carcinogenesis and lead to tumour. The PARP inhibitors can be used to exploit these tumour by inducing selective tumour cytotoxicity. This inhibition will cause generation of unrepaired DNA single strand breaks that will cause accumulation of DNA double strand breaks and the replication fork will collapse. A synthetic lethality will occur when between two non lethal events which is PARP inhibitor induces a DNA cut and a tumour which is lack of function for DNA repair pathway required to repair it. The best approach to treat breast cancer is by inhibiting the DNA repair enzyme in when the exogenous DNA damaging agent to kill tumour cell specifically absent.

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Its looks like new treatment for breast cancer is widely exploited and invented every day. Usually chemotherapy and radiotherapy was the only way to cure the breast cancer, but new findings shows that it can be cured by using different approach which will lead to invention of antibiotic.