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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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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 of those discussed in class, illustrate how the DNA damage response proteins contribute to carcinogenesis. How does this support CIN as an “enabling characteristic” of cancer cells? (10 points)

2. How would you propose to exploit genomic instability in cancer therapy? (6 points). Again—go beyond the notes.

3. Why are mutant tumor suppressor genes transmitted through the germline while mutant proto-oncogenes usually are not? (3 points)

4. The GTPase Ras is mutated in approximately 30% of all human cancers.

A) What is the most common mutation that converts the RAS proto-oncogene into an oncogene and why does this mutation render Ras oncogenic? (2 points)

B) Attempts to develop drugs that directly target mutant Ras have, for the most part, been unsuccessful. Why is this the case and what is one alternative strategy for inhibiting signaling pathways driven by oncogenic Ras? (3 points)

5. A point mutation within the coding sequence of an enzyme that confers gain-of-function is one well established mechanism for oncogene activation. Describe two other mechanisms of oncogene activation. For each mechanism, give a specific example that has been reported in cancer. (4 points)

6. If a mutant tumor suppressor gene (TSG) undergoes loss-of-heterozygosity in one out of 104 or 105 cells, and if an adult human is comprised of more than 1013 cells, why doesn’t a person who inherits a single mutant TSG develop thousands of tumors? (3 points)

7. Wilms tumor (pediatric nephroblastoma) can be caused by mutation of the WTX tumor suppressor gene. However, in contrast to classical tumor suppressor genes that require two “hits” for inactivation, WTX can be inactivated by a monoallelic “single-hit” event. Why is this the case for this particular TSG? (3 points)

8. You have identified a gene in the lab that you hypothesize is a novel tumor suppressor gene. Briefly outline a cell-based experiment to test your hypothesis. In your answer, define the criteria that need to be satisfied before you would be confident in classifying this gene as a TSG. (6 points)


Frank Purdue recently observed an increased morbidity and mortality rate at various chicken farms. Blood samples from sick chickens contained extremely elevated levels of abnormal lymphocytes, and these chickens eventually developed an incurable leukemia. 10 un-affected chickens were injected with serum derived from a leukemic chicken. Initially, all 10 chickens remained unaffected; however, by four months, 7 of these chickens began to develop leukemia. Electron microscopy of serum samples derived from leukemic chickens showed the presence of particles that were approximately 100nm in diameter. Incubation of cultures of primary chicken lymphocytes with serum from affected chickens resulted in the de novo synthesis of similar particles that were secreted from infected cells. Similar results were seen when cells were treated with serum that had first been filtered to remove all bacteria and fungi. Long term cultures of the infected, cultured lymphocytes continued to produce particles in the absence of obvious effects on cellular physiology. When particle-containing supernatants were treated with ether or chloroform and then added to cultured chicken lymphocytes, no newly synthesized particles were produced. Likewise, no particles were produced when these supernatants were added to cells that were subsequently treated with a combination of high levels of BUdr (bromodeoxyuridine) and ultraviolet light (cells were not killed by this treatment). Proteinase K treatment of concentrated supernatants revealed that the infectious particle contained a nucleotide genome; this genome was RNAse A sensitive. (NOTE: YOUR ANSWERS TO THE FOLLOWING 4 QUESTIONS CANNOT EXCEED TWO PAGES (IN TOTAL, NOT PER QUESTION); 0.5 INCH MARGINS, 12 POINT, SINGLE SPACE.

(1). The characteristics of the infectious agent described above support the hypothesis that it is a virus. What viral family does it likely belong to, and why? (Include in your answer the significance of “filterable agent”, sensitivity to chloroform, ether and BUdr/UV and the type of genome that is encapsidated—a general virology textbook and Howard Temin can help you answer this question). (20% of total points)

(2). Is it likely that this virus encodes a strong oncogene? How did you reach this conclusion? (15% of total points)

Using standard hybridization techniques, you demonstrate that the genome of your virus hybridizes with lymphocyte DNA extracted from chickens that have leukemia caused by this virus. However, the genome does not hybridize with non-lymphocyte cells derived from the leukemic chickens or with any cells, including lymphocytes, derived from uninfected chicken DNA.

(3). Why does the viral genome hybridize with lymphocyte DNA from the infected chickens and not with DNA from any other chicken cells (from either infected or uninfected chickens)? How do these hybridization studies support your answers to questions 1 and 2? (30% of total points)

(4). Provide a plausible hypothesis for how this infectious agent could cause leukemia. (Note that there is not necessarily an absolutely correct answer. One reasonable hypothesis is acceptable.) (35% of total points)

10. Discuss significance of cell cycle checkpoint studies to cancer therapy.

(Answer the following questions in a 1/2 - 1 page essay.)


(1). Describe similarities and differences among mismatch repair, base excision repair and nucleotide excision repair (3 points)

(2). Explain why deficiencies in transcription-coupled DNA repair leads to UV-sensitivity, but not to

cancer (3 points).

(3). Design experiments to test the involvement of a given protein in DNA repair, genomic stability and

tumorigenesis (4 points)

(4). Describe the role of oxidative DNA damage in predisposition to human cancer (4 points)

(5). Describe all experimentally proven connections of the system of homologous recombination and also non-homologous end-joining with tumorigenesis. Propose hypothetical connections, which don’t have experimental support but are consistent with known properties of these systems (Essay-10 points).


You have just performed a microarray analysis comparing genes expressed in normal tissue with tumor samples and got a list of genes regulating apoptotic pathways that are altered in the tumor tissue.

Refer to the list below:

Tumor 1 genes upregulated:


Tumor 2 genes downregulated:



TRAIL receptor

a. Explain the function of each gene in regulating apoptotic pathways (6 points).


1. Mechanism of action (including move cell closer to or farther from death threshold)

2. Does protein belong to intrinsic or extrinsic pathway?

b. Which of these tumors (Tumor 1 vs Tumor 2) would you expect to be more resistant to apoptosis induced by ionizing irradiation? Why? (1 points)

c. Your microarray picked up an unknown gene "DRGN1". Design an experiment to test whether this gene regulates apoptosis (be sure to include how you would measure apoptosis) (1 points)

d. Your results suggest that DRGN1 is a regulator of apoptosis. Design an experiment to test whether it regulates the intrinsic AND extrinsic death pathways. (2 points)


BH3 mimetics are thought to be potentially a breakthrough in anticancer therapy. Explain why (especially in the context of p53 status). (2 points)

(Can use diagrams to support written answer)

Answered Same Day Aug 06, 2021


Vidya answered on Aug 08 2021
134 Votes
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In the process of cancer development, the DNA damage and genetic instability plays a major role. The DNA lesions which are unrepaired or inco
ectly 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 e
ors, 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 ba
ier. 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
iefly 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.”
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
) 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
omodomain containing 4 (BRD4) are the examples of this strategy. These genes are involved in DNA damage response and replication stress pathways.
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 ca
ied 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
The other two mechanisms of oncogene activation are:
i. Gene amplification
ii. Chromosome rea
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).
ing chromosomal rea
angements are often detected in hematologic malignancies as well as in some solid tumors. These rea
angements consist mainly of chromosomal translocations and, less frequently, chromosomal inversions. Chromosomal rea
angements can lead to hematologic malignancy via two different mechanisms: (1) the transcriptional activation of protooncogenes or (2) the creation of fusion genes.
 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.
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.
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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