The Role Of BRCA-1 And BRCA-2 In DNA Repair And Implications For Cancer

The roles of BRCA-1 and BRCA-2 genes in DNA repair, and implications of mutations in these to cancers. The assignment must address the following:

(i) The structure and function of each of these genes and their encoded proteins.
(ii) The roles of these proteins in maintaining genomic integrity by DNA repair (giving their roles in at least one DNA repair system).
(iii) Examples of some common inherited mutations that have been associated with their loss of function, and mechanisms of inheritance (e.g., dominant/recessive, autosomal/X-linked; who may be affected; are the effects the same on everyone?)
(iv) The actual or expected effects of mutations/loss of function of these proteins.
(v) Examples of a molecular test to diagnose 1-2 common mutations in these, and the implications of a diagnosis of mutations in a person without symptoms.
(vi) Any ethical/ legal/ social benefits as well as concerns related to the genetic testing for BRCA-1 and BRCA-2, and a positive test for mutations (with or without diagnosis of actual cancer).

Neural differentiation of pluripotent stem cells. The essay must address the following:

(i) Different types of cells that can be used for neural differentiation (eg, pluripotent stem cells, neurals stem cells, transdifferentiation).
(ii) Background, main aims, key researchers, all main steps in work, the key observations, the principles / concepts related for neuronal differentiation. You may include key figure and/or tables for methods and results.
(iii) Outline any specific technical/scientific issues associated with this research.

Application of Third generation DNA sequencing such as SMRT, Tru-seq or nanopore techniques. The essay must address the following:
(i) Describe the principles of the third generation technology and how it differs from nextgeneration sequencing techniques. Who are the pioneering Scientists/Biotechnology companies behind this technique/technology?
(ii) Present at least one recent example of application of this technique. What were the results in this particular application and how were they analysed? You may include key figure and/or tables for methods and results. What advantages did this technique offer in this particular application?

BRCA-1 and BRCA-2 Genes in DNA Repair and Regulation

BRCA-1 and BRCA-2 (Breast Cancer 1 and 2) are genes in the human body that produce tumor suppressor proteins. This gene modulates and control the system of cell division in ensuring that cell occurrence is neither rapid nor out of control. They also help in the repairing of damaged DNA to ensure steady cell genetic material. In case of any alterations of these genes there will be genetic changes that will result in cancer. Some of the cancer that are mostly associated with BRCA-1 and BRCA-2 are mostly breast cancer, ovarian cancer and other types of cancer like fallopian tube, peritoneal cancer and prostate cancer among men and pancreatic cancer for both men and women, an example of. Mostly women are affected by this cancer if they inherited this problems from their parents (Finch et al., 2014). An example of a mutation for BRCA-2 is FANCD1 which is inherited form parents and can cause anemia associated with tumors and leukemia at early stages. (DNA)Deoxyribonucleic acid are nucleotides that carry genetic instructions used in the genetic growth and development in the living organism. This essay will understand the role of BRCA-1 and BRCA-2 in DNA repair and the implication of mutations in these to cancers.

• Structure and functions of BRCA-1and BRCA-2

BRCA 2 gene is composed of 27 exons almost twice the size of BRCA1 with approximately 3418 amino and 384kDAa(Syngal, 2015) .BRCA 1 and BRCA 2 are tumor suppressor genes that incase of mutation lead to cancerous diseases, some functions of this genes are :Firstly, They contribute to the repair of DNA genes and regulation of DNA  damage in living organisms, secondly they help  in the maintenance of chromosol stability thereby protecting chromosome from damage and embryo proliferation .Recent studies have shown that BRCA have helped in the regulation of DNA cell cycle and apoptosis. the main role of BRCA 2 is the regulation of the function of RAD 51 in repairing homologous recombination. BRCA 1 is mutated in three regions N terminal, BRCT domain and exons 11-13. BRCA 1 has undergone over 1700 mutations with 858 of this mutation being confirmed as deadly ones with the possibly of causing cancer, it consists of amino acids and zinc ions.

• The roles of BRCA-1 and BRCA-2 in maintaining genetic integrity by DNA repair

Carcinogenesis has been on the rise because of genetic mutation, this has resulted to lack of genes that are responsible for the maintenance of genome integrity. The damage of DNA has been attributed to direct damage and recombinational damages. BRCA 2 and BRCA 1 genes have taken part in the repairing of damaged DNA by association with other proteins in mending breaks in DNA (Subertilla et al. ,2015),BRCA 1 and 2 activate the repair of double strands breaks (DBS) thereby leading to the process of homologous recombination   (HR ) which thus links these breaks (Hortobagy et al., 2016),they also help in the formation of hinderances to the spread of damaged gene so that the damaged genes does not affect other important areas, breaks that can either be natural or as a result of medical emissions or problems with the environment changes, however it should be noted that damage repair pathways are necessary for growth and development of organisms except when the repair is defective from the normal repair, other error sin the DNA  include errors during DNA replication, errors as result of exposure of DA to chemical activities such as ionization radiation and oxidative stress among the cells (Tung et al., 2015).BRCA lack also causes abnormalities in the G2 checkpoint ,centrosome duplication and spindle checkpoint leading to destruction of DNA  which bocks cell proliferation inducing apoptosis, unless this tumors is broken unit will result to cancer (Baretta, Mocellin, Goldin, Olopade & Huo, 2016). The role of BRCA has also been attributed to phosphoryl action event, however this research has not yet been confirmed (Castro, 2015).

• Examples of common inherited mutation

The Implication of BRCA mutations in Carcinogenesis

Research has shown that the effects of alteration or mutation of this genes is rampant in women that in men thereby leading to cancer associated with mutation of this genes mostly in women. Inheritance of mutation in BRCA 1 and BRCA 2 occur in a pattern called autosomal dominance pattern (Haley, 2016).) where the mutated dominant gene is found in one of the autosomes, which means that if the father has a mutated gene there is fifty percent chance of one half of the children having cancer. It should also be noted that it is also not proven that only women can undergo inheritance though a large percentage has been seen in them and not all the people who have inherited this gene are guaranteed to have cancer (Suberbielle et al., 2015). The effect of this inheritance has been different with some people contracting other diseases like leukemia while other contract disease like cancer. An example of a serious inheritance mutation is Fanconi anemia which is inherited from parents it is associated with tumors during childhood and leukemia.

• Effects of mutation

The sequence of a DNA can be changed in several ways and all this mutations have a number of effect on the health of the organism in which they occur in, even as more studies are being taken it has been noted that BRCA1 and 2 can alter in more than 500 ways within which some implications are not known, according to statistics at the age of 70 years there is 60% risk of those with BRCA mutations having breast cancer which causes sexual dysfunctions (Barretta et al., 2016),lack or poor of sleep and hormonal (menopausal) imbalance while statistics show that occurrence of ovarian cancer whether it is inherited or from gene modification that is developed after birth  is at 49% specifically for the ladies (Tung et al., 2015). It has also been indicated that with gene mutation there are several other diseases and cancers that will develop from this deficiency such as anemia and leukemia, some scholars have also proven the relationship between this mutations with tumor suggesting that this mutations could result to tumor in the organism affected (Hortobagyi et al., 2016). Mostly the effect of mutation is alteration OF DNA resulting to cancer specifically of the breast and ovary for women and prostrate for men (Castro, Goh, Leongamornlert, Saunders, Tymrakiewicz, Dadaev & Bancroft, 2015).

• Molecular test to diagnose common mutation

There are several ways of testing and recognizing the presence of BRCA mutation .BRCA2 is twice greater than BRCA1 containing 27 exons and approximately 3418 amino acids and with this property there are methods that can be used in the detection of mutation in only BRCA 1 or 2 (Hortobagyi et al., 2016). Multigene or panel testing is used in testing for the mutation in the genes that is attributed to BRCA 1 or BRCA 2 most those that are associated with breast and ovarian cancer (Fiche et al. 2014). The sample that is used in this testing is mostly DNA from saliva or blood (Syngal et al., 2015). There are also reference tools that are used in the process of screening breasts for cancer which is associated with cancer example the use of MRI (Magnetic Resonance Imaging) in carrying out annual breast examinations.

• Benefits of genetic testing

Testing for BRCA mutations and recognition

Genetic testing has proven to be helpful regardless of the outcome of the result whether positive or negative as explained by gene mutation (Field & Goff, 2018). When the result is positive indicating gene mutation the affected person will seek medical attention in attempts to print further spread of cancer and also for provision of tests (Takaoka & Miki, 2018). When the results are negative of gene mutation a person can freely stop bothering about their gene mutation and also in avoiding unnecessary checkups and screenings. In the young new born it will help with prior planning on how to deal with the issue even as the person will grow old to face diseases because of cancer (Haley, 2016).

Conclusion

In conclusion, it can be noted that there is a significant role of BRCA1 and BRCA 2 in the repair of DNA. Absence of BRCA1 and BRCA leads to cancer. There is need for carrying out genetic tests since regardless of the results and some common examples of mutations a result of this mutation is cancer, leukemia and anemia.

Reference

Baretta, Z., Mocellin, S., Goldin, E., Olopade, O. I., & Huo, D. (2016). Effect of BRCA germline mutations on breast cancer prognosis: a systematic review and meta-analysis. Medicine, 95(40).

Castro, E., Goh, C., Leongamornlert, D., Saunders, E., Tymrakiewicz, M., Dadaev, T., ... & Bancroft, E. (2015). Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. European urology, 68(2), 186-193.

Field, C., & Goff, B. A. (2018). Dermatomyositis-key to diagnosing ovarian cancer, monitoring treatment and detecting recurrent disease: Case report. Gynecologic oncology reports, 23, 1-3.

Finch, A. P., Lubinski, J., Møller, P., Singer, C. F., Karlan, B., Senter, L., ... & Huzarski, T. (2014). Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. Journal of Clinical Oncology, 32(15), 1547.

Haley, B. (2016). Hereditary breast cancer: the basics of BRCA and beyond.

Hortobagyi, G. N., Chen, D., Piccart, M., Rugo, H. S., Burris III, H. A., Pritchard, K. I., ... & Shtivelband, M. (2016). Correlative analysis of genetic alterations and everolimus benefit in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from BOLERO-2. Journal of Clinical Oncology, 34(5), 419.

Suberbielle, E., Djukic, B., Evans, M., Kim, D. H., Taneja, P., Wang, X., ... & Masliah, E. (2015). DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nature communications, 6, 8897.

Syngal, S., Brand, R. E., Church, J. M., Giardiello, F. M., Hampel, H. L., & Burt, R. W. (2015). ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. The American journal of gastroenterology, 110(2), 223.

Takaoka, M., & Miki, Y. (2018). BRCA1 gene: function and deficiency. International journal of clinical oncology, 23(1), 36-44.

Tung, N., Battelli, C., Allen, B., Kaldate, R., Bhatnagar, S., Bowles, K., ... & Krejdovsky, J. (2015). Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next?generation sequencing with a 25?gene panel. Cancer, 121(1), 25-33.