1. Describe in detail the relationships between the DNA damage response and genomic instability—distinguish between numerical, structural and mutational instability. Using sources and examples outside...

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Answered Same DayAug 06, 2021

Answer To: 1. Describe in detail the relationships between the DNA damage response and genomic...

Vidya answered on Aug 08 2021
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GENETICS
Order No. 63005
1.
In the process of cancer development, the DNA damage and genetic instability plays a major role. The DNA lesions which are unrepaired or incorrectly repaired may lead to the mutations that are cancer-initiating or cancer-driving. On the other hand, the genomic instability works by fueling the tumor progression which is a multistep process and also by developing resistance to the therapy. Hence, these are the heart of cancer development. Iatrogenic sources of DNA damage that includes chemotherapy and radiotherapy can also destabilize the genome and induce mutations apart from the endogenous sources like oxidative stress and fortuitous replication errors, and exogenous insults of cigarette smoke or UV light. This can occasionally lead
to secondary malignancy developments or allows to select the treatment-resistant cancer cell clones within the tumors that were initially therapy-responsive.
The chromosomal instability occurs when there is continuous mutations of the novel chromosome, which happens at a higher rate than that happens in the normal cells. This instability can occur as numerical, structural or mutational instability. This involves the processes of inversions, deletions, translocations and amplifications of chromosomal regions which ranges in size from single genes to the whole chromosome arms.
Carcinogenesis is a multistep process. It begins with the dysregulation of cell proliferation which then triggers the DNA damage response. This activation causes disposal of precancerous cells, posing the cells for repair, senescence, or cell death. Hence it delays or avoids uncontrolled cell growth and carcinogenesis. In the progression from pre-neoplastic abnormalities to cancers, the loss of DNA damage response capabilities diminishes the above barrier. At the same time, a cell with DDR deficiency indeed displays higher genomic instability and increased dependency on remaining DDR pathways, leading to a worse outcome during its DNA repair. This vicious circle overloads threats on the genome of the cell that may initiate its carcinogenesis.
On a wider view, this relationship can be formulated briefly as: “The cellular and molecular principles of the DNA damage response should be understood, in order to understand cancer. The roles of DNA damage and genetic instability in carcinogenesis and the tumor responses to the therapeutic modalities based on the DNA damage response should also be known to optimize the already existing treatments or to design new targeted therapies on molecular level.”
2.
As chromosomal instability plays a major role in the progression of carcinogenesis, targeting this would be more helpful in overcoming the tumor heterogenecity. The strategies that induce CIN to unsustainable levels could be the main approach. This can be done through two ways:
a) CIN-inducing therapy
b) CIN-reducing therapy
The first approaches through instigating the mitotic catastrophe by targeting critical cellular machinery. Some traditional chemotherapeutic agents are found to act by CIN-inducing mechanisms because the cancer cells cannot tolerate and repair genetic insults as better as the normal cells do.
If the CIN genes that dysregulate in cancer can be directly targeted, then also it could be exploited. DNA topoisomerase I (TOP1), Ataxia-telangiectasia mutated (ATM) and bromodomain containing 4 (BRD4) are the examples of this strategy. These genes are involved in DNA damage response and replication stress pathways.
3.
Tumor suppressor genes are the normal genes that slows down the process of cell division, DNA repairing and promote apoptosis or programmed cell death. Cancer tissues are formed when these genes does not work properly, leading to excessive normal cell growth. Proto-oncogenes are the genes that help the cells in normal growth. But when it undergoes mutation, it gets activated and the cells grow out of control. Upon activation, it is called as oncogene. The major difference is that oncogenes are formed by the activation of proto-oncogenes, whereas tumor suppressor genes cause cancer when they are in the inactivated state.
The tumor suppressor gene gets transmitted through the germline as it can be inherited. In these mutations, a copy of the gene pair is carried from a parent. But proto-oncogenes undergo the changes upon activation during the normal cell growth.
4. (a)
The most common mutation that converts the RAS proto-oncogene into an oncogene occur by point mutation, gene amplification, and gene translocation. An activating mutation of one of the two alleles of a proto-oncogene converts it to an oncogene, which can induce transformation in cultured cells or cancer in animals.
This cancer-causing mutation of Ras creates a continuous form of protein which continually multiplies the cancer cells without the normal limits that control cell growth.
4. (b)
The attempts to develop drugs that directly target mutant Ras have been unsuccessful mostly because they have relative cellular abundance of GTP. They also have extremely high affinity for GTP binding.
The presence of Ras signaling in various kinds of tumors in humans has made it crucial to develop therapeutic agents that can restore the normal functioning of tumor cells. The indirect inhibition of Ras effectors such as MEK-1/2, Raf, PI3K, AKT, etc. are the main targets in the process. It is categorized as follows:
i. Prevention of Ras-GTP Formation
ii. Covalent Locking of the GDP-bound State
iii. Inhibition of Ras-effector Interactions
iv. Impairment of Post-translational Modification of Ras
5.
The other two mechanisms of oncogene activation are:
i. Gene amplification
ii. Chromosome rearrangements
Gene amplification refers to the expansion in copy number of a gene within the genome of a cell. Gene amplification was first discovered as a mechanism by which some tumor cell lines can acquire resistance to growth-inhibiting drugs. The process of gene amplification occurs through redundant replication of genomic DNA, often giving rise to karyotypic abnormalities called double-minute chromosomes (DMs) and homogeneous staining regions (HSRs).
Recurring chromosomal rearrangements are often detected in hematologic malignancies as well as in some solid tumors. These rearrangements consist mainly of chromosomal translocations and, less frequently, chromosomal inversions. Chromosomal rearrangements can lead to hematologic malignancy via two different mechanisms: (1) the transcriptional activation of protooncogenes or (2) the creation of fusion genes.
6.
 Tumor suppressor genes represent the opposite side of cell growth control, normally acting to inhibit cell proliferation and tumor development. In many tumors, these genes are lost or inactivated, thereby removing negative regulators of cell proliferation and contributing to the abnormal proliferation of tumor cells.
Both copies of a specific tumor suppressor gene pair need to be mutated in order to cause a change in cell growth and tumor formation to happen. For this reason, tumor suppressor genes are said to be recessive at the cellular level.
7.
In contrast to the classical tumor suppressor genes that require two “hits” for inactivation, WTX can be inactivated by a monoallelic “single-hit” event. This happens as it targets the single X chromosome in tumors from males and the active X chromosome in tumors from females.
Tumors with mutations in WTX lack WT1 mutations, and both genes share a restricted temporal and spatial expression pattern in normal renal precursors.
8.
To test the hypothesis of confirming a novel tumor suppressor gene, the following experiment can be performed.
Pan-cancer analysis can be used to examine the...
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