1. Discuss how both spontaneous mutation events and different mutagens chemically modify DNA. What other modifications are important that do not involve changes in DNA sequence?
A mutation is a permanent change in the genetic material of an organism that is heritable. This alteration entails a change in the genome’s nucleotide sequence by changing a base or multiple bases. Mutations can occur spontaneously, or they may be the result of the interaction of DNA with certain physical and chemical agents in the environment. Spontaneous mutations occur without the influence of external agents and may result due to errors in genome replication, errors caused by the mechanism of DNA repair, or spontaneous lesions. On the other hand, induced mutations occur when DNA comes into contact with physical or chemical agents, commonly known as mutagens. Chemical mutagens include chemical agents such as hydroxylamine while physical mutagens include forms of radiation such as ionizing gamma radiation and ultra-violet light (Vogelstein et al., 1547).
Spontaneous mutation events and different mutagens modify DNA chemically in various ways leading to various changes in DNA sequence. There are five major types of mutation: substitution, deletion, insertion, inversion, and duplication. In substitution, a base pair replaces another base pair on the DNA molecule. Substitutions are further classified into two types: transitions and transversions. A transition is the replacement of a purine by the other purine (G → A or A → G) or a pyrimidine by the other pyrimidine (C → T or T → C). On the other hand, a transversion is the replacement of a purine by a pyrimidine or vice versa. An insertion results upon the addition of one or more extra base pairs into a new location in the DNA molecule while deletions are mutations that involve the loss of a section of DNA. In inversion mutations, the nucleotide sequence in a portion of DNA undergoes end to end reversal. For example, TGC becomes CGT. Finally, duplication occurs when a portion of DNA undergoes abnormal copying one or more times resulting in dysfunctional or nonfunctional proteins (Blakeslee, 259 – 263).
Chemical modification of DNA due to spontaneous mutations and exposure to mutagens occurs in various ways. Firstly, some mutagens bring about a base change through covalent modifications. Examples of such mutagens are alkylating agents like Benzo[a]pyrene and ethylene oxide. Benzo[a]pyrene alkylates guanine residues in DNA causing a distortion in its helical structure. When the distorted DNA molecule is replicated, it contains an insertion. Similarly, ethylene oxide alkylates guanine residues albeit through ethylation, with the product being ethylguanine. Subsequently, the mutation results from the mispairing of altered guanine residue (Martincorena and Campbell, 1485). Some mutagens such as nitrogen mustard and carmustine induce cross-linking of DNA strands. They react with two separate positions in the DNA molecule, causing either intrastrand cross-linking or inter-strand cross-linking if they occur on the same strand or in opposite strands respectively. UV and X-ray radiation can cause mutations in three main ways. Firstly, they can bring about the fragmentation of DNA. Secondly, they can cause thymidine dimerization through covalent bond formation. Thirdly, radiations can cause the equilibrium of the tautomeric forms of bases to shift. This shift in equilibrium causes mutation by impairing base pairing since the minor and major tautomers differ in base-pairing properties (Stratton, Campbell, and Futreal, 721).
Spontaneous mutations sometimes result from spontaneous chemical changes that cause lesions. The most common spontaneous chemical changes are depurination, deamination, and oxidation. Depurination occurs when the glycosidic bond between the deoxyribose and the base breaks leading to the loss of an adenine or a guanine residue. Mammalian cells tend to lose an average of 10,000 purines from their DNA spontaneously in a cell-generation period of 20 hours. Sustained depurination causes considerable genetic damage as the ensuing apurinic sites disrupt codons. DNA repair mechanisms remove these apurinic sites, but sometimes they err resulting in deletion mutations during replication (Chakarov, Petkova, Russev, and Zhelev, n.p.).
The second most common spontaneous chemical change, deamination, occurs when cytosine loses an amine group yielding uracil. DNA repair mechanisms sometimes fail to reverse this change, in which case the uracil residue pairs with adenine when DNA replicates, leading to the formation of an A-T pair rather than a G-C pair. Finally, spontaneous mutations can occur due to oxidative damage to bases. Oxidation of bases occurs when normal aerobic metabolism yields active oxygen species such as hydrogen peroxide and superoxide radicals, which can inflict oxidative damage on DNA as well as DNA precursors like GTP, causing mutations (Chakarov, Petkova, Russev, and Zhelev, n.p.).
Apart from gene mutations, there are other modifications to the DNA molecule that do not involve changes in its sequence. In eukaryotes, the DNA contains extra information in addition to the genes, which directs the splicing machinery to the appropriate points of commencement and termination of splicing. These portions of DNA that occur outside the coding sequences include enhancer or promoter sequences, termination signals, splice acceptor and donor sites, and ribosome binding sites. Mutations in these regions can affect gene expression by changing the amount of a protein the cell produces rather than changing the function of that protein. For instance, mutations in a promoter sequence can result in stronger or weaker binding of RNA polymerase to the promoter leading to increased or decreased frequency of transcription respectively. Therefore, “up” promoter mutations increase the production of a particular protein while “down” promoter mutations decrease its production (Chakarov, Petkova, Russev, and Zhelev, n.p.).
2. What are the general phenotypic characteristics of cancer cells that distinguish them from normal tissues? What gene mutations are associated with these phenotypes?
Cancer cells display various phenotypic characteristics that distinguish them from normal cells and tissues, which include:
- Unchecked multiplication and growth
- Invasion of neighboring tissues
- Lack of specialization
- Inability to undergo programmed cell death
Firstly, cancer cells reproduce uncontrollably unlike normal cells, which reproduce only in response to controlled signals from the cell that instruct them to multiply to replace aged or damaged cells. Also, normal cells multiply orderly by the phases of the cell cycle, but cancer cells multiply throughout irrespective of the phase of the cell cycle in which they are. Cancer cells can reproduce uncontrollably due to gene or chromosomal mutations that alter their reproductive properties. These mutations allow the cells to gain control of their growth signals enabling them to multiply unchecked (Hanahan and Weinberg, 647).
Secondly, cancer cells lack the adhesion molecules that keep normal cells attached to neighboring cells. Consequently, cancer cells tend to spread to adjacent tissues and even metastasize to distant tissues and organs in many parts of the body via the blood and lymph fluid. In contrast, normal cells stay in their appropriate location because they have adhesion molecules that allow them to recognize other cells of a similar type and bond to them (Hanahan and Weinberg, 649).
Thirdly, cancer cells are not specialized for any specific cell function. Their morphology and physiology resemble that of stem cells and, consequently, it is no surprise that cancer cells replicate numerous times and for extended periods like stem cells. In contrast, normal cells develop into cells that are specialized for particular functions such as nerve cells, lung cells, and muscle cells. Finally, cancer cells are immortal. They have lost susceptibility to apoptosis and, consequently, they cannot undergo programmed cell death when they become diseased or aged (Hanahan and Weinberg, 649).
Mutations to three main classes of genes are responsible for the development of the phenotypic characteristics that distinguish cancer cells from normal cells. These genes include oncogenes, tumor suppressor genes, as well as DNA repair genes. Oncogenes are damaged or mutated versions of normal genes known as proto-oncogenes, which control various cell functions that relate to the growth, reproduction, and differentiation of cells. Oncogenes promote the transformation of normal cells to cancer cells by causing them to grow out of control. The transformation of proto-oncogenes to oncogenes disrupts the balance of cell cycle regulation, predisposing the cell to uncontrolled growth. Additionally, oncogenes can cause cells selected for apoptosis to avoid it and proliferate instead. An example of an oncogene is the ras oncogene, which is implicated in up to 30% of all tumors that occur in humans (Coussens and Hanahan, 312 – 313). Therefore, the mutation of oncogenes promotes the inability to undergo apoptosis, prevents specialization, and encourages unchecked proliferation in cancer cells.
Tumor suppressor genes help to protect the cell against cancer. They code for anti-proliferation proteins and signals that suppress cell growth as well as mitosis. They tend to be activated by DNA damage and cellular stress and help to control cell death as well as arrest the growth of cells. The primary function of tumor suppressor genes is to halt the cell cycle’s progression to allow DNA repair mechanisms to repair damaged or mutated DNA and, consequently, prevent daughter cells from inheriting mutations. Mutations in tumor suppressor genes remove the brakes on cell growth and cell division and impair apoptosis. Consequently, such mutations encourage the development of cancer cells. The TP53 gene is an example of a tumor suppressor gene, which codes for the p53 tumor suppressor protein (Coussens and Hanahan, 316).
DNA repair genes help to fix mutations that commonly arise during DNA replication. Damage to DNA repair genes allows mutations to persist and build up, predisposing cells to cancerous transformation. These genes help to safeguard all other genes against mutation, including proto-oncogenes and tumor suppressor genes. Consequently, their damage allows proto-oncogenes to develop into oncogenes and tumor suppressor genes to become ineffective, causing the expression of cancerous phenotypic characteristics by the cell. An example of a DNA repair gene is the SMUG1 gene, which corrects mutations through base excision repair (Vogelstein et al., 1544).
3. Describe the key role of Rb in the regulation of the cell cycle.
The retinoblastoma (Rb) protein serves as a tumor suppressor that plays a crucial role in the negative regulation of the cell cycle. The Rb protein controls a key G1 checkpoint, preventing progression of the cell cycle from the G1 phase to the S phase. In this way, it restricts the ability of the cell to replicate DNA. A cell only proceeds from the G1 phase to the S phase when the E2F family of transcription factors complexes with a dimerization partner (DP) protein. When Rb binds to E2F it inactivates the E2F-DP complex and, consequently, the cell cannot move from G1 to the S phase. The Rb-E2F-DP complex acts as a growth suppressor that prevents the cell from progressing through the cell cycle. The Rb-mediated suppression of the cell cycle is only eased when the cell receives external signals such as growth factors informing it to proceed to the S phase. These external signals bring about this effect by activating the G1 cyclin/Cdk complex. The activated G1 cyclin/Cdk complex phosphorylates the Rb protein, the effect of which is the release of Rb from E2F. This release allows the E2F transcription factors to facilitate the synthesis of a variety of proteins that are necessary for the synthesis of DNA during the S phase. One of these proteins is cyclin E, which binds to Cdc2 kinase forming a complex that fires DNA replication (Giacinti and Giordano, 5221 – 5222).
The Rb’s function as a brake of the cell cycle does not only entail the inhibition of the E2F-DP complex but also by the suppression of DNA synthesis through remodeling of the structure of chromatin. Rb brings about chromatin remodeling in three ways. The first one involves interacting with the hBRM protein to modulate nucleosome remodeling. The second method involves interacting with the BRG1 protein to modulate histone acetylation/deacetylation. In particular, it attracts histone deacetylase to the chromatin and, subsequently, suppresses the transcription of S-phase-promoting factors. Finally, Rb causes chromatin remodeling by interacting with the SUV39H1 protein which is involved in methylation (Serrano, Hannon, and Beach, 705).
The loss of the functions of Rb can potentially cause cell cycle deregulation leading to the development of a malignant phenotype. The fact that the inactivation of genes that code for the Rb protein due to chromosomal mutations is one of the etiological factors of retinoblastoma tumor development is evidence of this assertion. Additionally, many neoplasms such as AIDS-related Burkitt’s lymphoma, mesothelioma, and cervical cancer display functional inactivation of Rb through the binding of viral oncoprotein, providing further evidence of the role of the loss of Rb function in the development of neoplasms (Giacinti and Giordano, 5225).
4. Cancer cells are often mutated in p53. Why is the normal function of this gene so important? Outline how p53 controls cell cycle progression when there is DNA damage.
The fact that cancer cells often display mutations in the p53 gene shows that this gene plays a vital role in cancer prevention.The p53 transcription factor undergoes activation when the cell experiences stress. Apart from damage to DNA, p53 can be activated by oxidative stress, metabolic stress, ribosomal stress, viral infection, and telomere shortening, all of which are potential precursors to oncogenic activity. However, the ability of p53 to arrest cell cycle progression when DNA damage occurs is of utmost importance. DNA damage and any other oncogenic activity tend to interfere with normal cellular physiology causing cellular stress which activates p53. Therefore, it is no surprise that the p53 pathway is usually disrupted in neoplastic cells. In normal cells that have not been subjected to stress, p53 levels are very low because its degradation is efficient. The MDM2/MDMX complex is key to the suppression of p53 levels. MDM2 is an E3 ligase that ubiquitinates p53 and, consequently, targets it for degradation by a proteasome or subsequent nuclear export. A variety of other ubiquitin ligases like ARFBP1 can also ubiquitinate p53 and designate it for degradation, providing an alternative check on the levels of p53 when the cell has not experienced DNA damage (Langerak and Russell, 3563 – 3564).
However, DNA damage and other forms of oncogenic stress reduce the activity of MDM2 towards p53 through a variety of ways. Firstly, proteins such as L5/L11 ribosomal proteins and ARF bind to MDM2 and prevent it from ubiquitinating p53. Alternatively, the DNA damage-dependent kinases ATM and ATR phosphorylate p53 and MDM2 on serine 15 preventing the interaction of MDM2 with p53. Additionally, the CHK1 and CHK2 kinases can phosphorylate serine 6, 9, 18, 20, and 33 on p53 resulting in the disruption of the MDM2-p53 complex. All these pathways serve to increase the levels of p53 upon exposure of the cell to stress or DNA damage. In turn, p53 helps the cell to cope with the stress in one of a variety of ways depending on the source of the stress. Its effects range from a permanent arrest of the cell cycle, cell death, repair of damaged DNA, to metabolic stress adaptation (Langerak and Russell, 3566).
When DNA is damaged, p53 binds to DNA activating a gene that codes for a protein called p21. In turn, p21 binds to and inhibits cdk2, a cell division-stimulating protein, preventing the cell cycle from proceeding to the stage of cell division. This cell cycle arrest provides the cell with the time to fix DNA damage and prevent this damage from being passed on to daughter cells culminating in tumor-inducing mutations. p53 not only provides the cell with the time to fix DNA damage but also the means to fix it by inducing tumor repair genes. In cases whereby DNA damage is too severe for repair mechanisms to reverse it, p53 terminates the cell cycle by inducing senescence-mediating genes like Pai1, dec1, and DcR2 or activating apoptosis-mediating receptors and proteins like DR5 and Noxa respectively (Wang et al., 13069).
5. How is it that viruses, in general, may cause cancer? What do we know about the specific molecular changes that HPV AND the hepatitis virus cause that may result in cancer?
Some viruses can cause certain cancers in humans. For instance, human papillomavirus can cause cervical cancer. The link between viruses and cancer is based on the fact that they lack reproductive mechanisms and, therefore, must infect living cells and hijack their machinery to make more viruses. They contain few genes as either DNA or RNA and must insert their genetic material into host DNA to instruct the cell’s machinery to synthesize viral components (Moore and Chang, 879).
Viral genes can induce the development of a malignant phenotype in three main ways. Firstly, some viral genes code for proteins that push the cell cycle into overdrive leading to continuous cell division. Secondly, some viral genes, when incorporated into host DNA, code for proteins that inhibit tumor suppressor proteins. Thirdly, some viral genes, when inserted into the host DNA, disrupt genes that play a crucial role in the control of the cell cycle. The primary purpose of these viral-mediated processes is to force an unscheduled entry of the cell into S phase to allow the cell to generate the resources that are necessary for viral replication (Moore and Chang, 882). Consequently, the cell loses control of the factors that control the cell cycle. In short, viruses can cause cancer because they are obligatory intracellular parasites that encode proteins which reprogram the host’s cellular signaling pathways that regulate proliferation, growth, differentiation, cell death, and genomic integrity.
Only 30 strains of the more than 100 strains of human papillomavirus (HPV) can cause cervical cancer (McLaughlin-Drubin and Munger, 133). When HPV infects basal epithelial cells in the cervix, it inserts genes that encode the HPV E7 oncoprotein into the host DNA. The HPV E7 binds and inactivates the retinoblastoma (Rb) tumor suppressor protein, allowing the cell cycle to proceed to S phase unchecked and, consequently, allow viral genome replication. Simultaneously, some of the HPV genes encode the HPV E6 protein, which stimulates ubiquitin-mediated degradation of the p53 tumor suppressor, preventing the cell from undergoing premature apoptosis that would terminate viral reproduction (Mazumder et al., 601). These two changes may result in cancer.
The link between the hepatitis viruses (B and C) and liver carcinogenesis is apparent, but the mechanisms through which it ensues are unclear. One theory holds that the ensuing liver cirrhosis contributes to hepatocellular carcinoma because constant necrosis of hepatocytes spurs rapid regeneration, which may result in the build-up of mutations predisposing hepatocytes to carcinogenesis. Other studies have singled out the viral regulatory protein HBx, which enhances cell proliferation and viability and, therefore, possibly contributes to the carcinogenicity of the hepatitis B virus. Some hepatitis C virus proteins have also been reported to inactivate tumor suppressors like p53 and activate cellular oncoproteins (Moore and Chang, 887 – 888).
6. Outline the role of the RAS signaling pathway in normal cells and cancer.
RAS is a type of small GTPase proteins that are involved in cellular signal transduction. RAS proteins such as NRAS, HRAS, and KRAS serve as binary molecular switches whose primary purpose is to control signaling networks at the cellular level. These signaling pathways control a variety of cellular processes including cell proliferation, cell adhesion, cell differentiation, cell migration, apoptosis, and cytoskeletal integrity. Incoming signals switch on RAS proteins, which then activate other proteins that turn on genes that are involved in the above processes (Zenonos and Kyprianou, 97).
RAS proteins activate several pathways, including the mitogen-activated protein kinase (MAPK) cascade and the phosphoinositide-3 kinase (PI3K) pathway. The MAPK cascade culminates in the transcription of genes that are central to cell proliferation. It commences when an external ligand such as epidermal growth factor binds to a tyrosine kinase receptor to trigger a cascade of phosphorylation events and activations that lead to the activation of RAS proteins by guanosine triphosphate molecules. In turn, RAS proteins activate the MEK protein which then activates ERK through phosphorylation. ERK enters the nucleus where it activates several transcription factors such as Fos and Jun, which activate genes that facilitate cell proliferation (Zenonos and Kyprianou, 98 – 100).
On the other hand, the PI3K pathway stimulates cellular growth and the inhibition of apoptosis. It is also triggered by the binding of growth factors to tyrosine kinase receptors. The resulting cascade activates RAS, which binds to the p110 subunit of a PI3K protein such as IA. PIK3 triggers a subsequent cascade that culminates in the phosphorylation of AKT, which generates signals that facilitate the evasion of apoptosis and stimulate cellular growth (Vojtek and Der, 19926).
Mutations relating to RAS signaling pathways can result in cancer due to the important roles that these pathways play regarding cell proliferation, cell differentiation, cell adhesion, and the inhibition of apoptosis. Mutations involving RAS genes can result in the permanent activation of RAS proteins causing overactive signaling of RAS pathways. RAS oncogenes account for up to 25% of all tumors in humans, a finding that is not surprising considering that RAS proteins often display deregulation in human cancers culminating in uncontrolled proliferation, decreased apoptosis, and increased invasion as well as metastasis. Mutations that activate oncogenes that are upstream in the RAS signaling pathway like p210BCR-ABL are major culprits in carcinogenesis. Additionally, some mutations lock RAS in a permanently active state by preventing GTP hydrolysis. These mutations commonly affect the catalytic residue Q61 or the P-loop’s residue G12, contributing to overactive RAS signaling and subsequent malignant phenotypes (Zenonos and Kyprianou, 100).
7. Describe the molecular rationale for the use of PARP inhibitors and describe a molecular approach to identify suitable patients for these drugs.
The 17-member poly (ADP-ribose) polymerase (PARP) protein family is found in the nucleus and is responsible for mediating several crucial cellular processes including DNA repair, genomic stability, and apoptosis. PARP1 and PARP2 are targets of anticancer agents because of the central role they play in DNA repair. DNA molecules undergo damage regularly due to constant exposure to endogenous and exogenous cellular stress factors. PARP1 and PARP2 provide the cell with the mechanism for detecting and repairing this damage since they are major components of the base excision repair (BER) pathway. They help to repair single-strand DNA breaks by binding to the affected site on DNA and initiating the synthesis of poly (ADP-ribose) chain, which signals other repair proteins to the site of damage. These repair proteins, such as the scaffolding protein XRCC1 and the enzymes DNA ligase III and DNA polymerase beta, repair single-strand breaks before DNA replication. If replication occurs before the repair of the single-strand nicks, double-strand breaks occur in the DNA leading to eventual cell death (Brown, Kaye, and Yap, 713 – 714).
Anticancer agents that serve as PARP inhibitors, such as olaparib, take advantage of the fact that cancer cells display a greater dependence on PARP than normal cells. Inhibition of PARP leads to the impairment of single-strand DNA repair culminating in double-strand breaks. In cancer cells that have undergone mutations in PALB2, BRCA1, and BRCA2, the cell lacks the ability to repair double-strand breaks efficiently leading to cell death. In contrast, these genes function normally in noncancerous cells, which can repair double-strand breaks efficiently because their homologous repair is still operational (Comen and Robson, 49).
Currently, the only reliable molecular approach available for identifying cancer patients who are suitable for PARP inhibitors is the determination of the level of genomic instability that is associated with mutations in BRCA1 and BRCA2, which serve as measures of homologous repair deficiency. Only cancer cells that have lost homologous recombination repair ability due to mutations in BRCA1 and BRCA2 are unable to repair the double-strand breaks that result from PARP inhibition. Therefore, the homologous recombination deficiency (HRD) score is ideal for identifying patients who are adequately responsive to PARP inhibitors (Cerrato, Morra, and Celetti, 179). This score determines the level of BRCA1/2 mutations and, consequently, the level of genomic instability in cancer patients. It involves the use of a sequencing assay that measures homologous repair deficiency in DNA extracted from tumor cells. An HRD score equal to or greater than 42 indicates that the patient has sufficient responsiveness to PARP inhibitors (Azvolinsky, 1851 – 1852).
8. How has it been determined that tumors are not clonal as originally thought? What is the clinical significance of these findings? How do the experts weigh in on what to do about it?
A clone is a cell or a group of genetically identical cells or organisms that arose through asexual reproduction from a single ancestor, such as a single cell, to which they are all genetically identical. The original belief that tumors are clonal has been discounted after it emerged that tumors are heterogeneous. Neoplastic tumors arise from one cell, but they tend to demonstrate heterogeneity and contain different types of cells (Shackleton, Quintanal, Fearon, and Morrison, 823). Therefore, cells of the same tumor do not always carry similar genetic anomalies.
Scientists discovered that tumor cells are heterogeneic rather than clonal by observing different phenotypic and morphological profiles between cells of the same tumor such as cellular morphology, proliferation, metastatic potential, motility, and gene expression. Although tumors arise from one cell or group of cells that have acquired a particular mutation, they accumulate more mutations as the cells continue to proliferate and the tumor grows (Shackleton, Quintanal, Fearon, and Morrison, 825). Consequently, the accumulation of mutations occurs with each successive generation, giving rise to tumor cells that are genetically and phenotypically distinct from the original cancerous cell.
The clinical significance of tumor heterogeneity is that it poses considerable challenges to the design of treatment strategies that are effective against various forms of cancer. Lack of clonality means that tumors tend to exhibit resistance to treatment because antitumor agents fail to kill all cells in heterogeneic tumors. The drug-resistant tumor cells that survive proliferate into a new tumor, which displays a higher level of aggression than the initial tumor. Consequently, researchers face the challenge of designing more refined treatment approaches that have a higher efficacy (Kaiser, 1543 – 1544).
Experts are approaching the problem of tumor heterogeneity by investigating methods of getting an accurate picture of heterogeneity at the onset of treatment and tracking clonal evolution during treatment to overcome drug resistance. Some of the methods under investigation to this end include multiregional sampling, longitudinal sampling, and genome-wide profiling. Multiregional sampling involves analyzing samples from different parts of a tumor during pre-treatment biopsy while longitudinal sampling involves obtaining and analyzing biopsy samples periodically during treatment. The genome-wide approach involves the analysis of the whole genome of samples obtained from tumors. In combination, these three strategies can provide an accurate representation of genetic composition and gene expression in heterogeneic tumors, allowing experts to design more effective treatment strategies against cancer (Liu, 1493).
9. Outline one or more pathways normally regulated by MYC and discuss why mutations in this gene can lead to cancer.
The Myc proto-oncogene is a crucial regulator of cell proliferation, growth, differentiation, as well as apoptosis. It encodes a transcription factor that serves as a vital component of many signal transduction pathways that promote growth. One of these pathways is the MAPK/ERK pathway, which controls cell proliferation. The MAPK pathway commences with the binding of a ligand like epidermal growth factor to receptor tyrosine kinase, which triggers a phosphorylation cascade that leads to the activation of ERK. ERK enters the nucleus and activates the Myc transcription factor which binds to the enhancer box sequence CAC(G/A)TG leading to the transcription of genes that play an important role in cell proliferation. Myc can also suppress proliferation through the MAPK pathway by displacing histone acetyltransferase p300, preventing it from binding to the CREB protein. Consequently, it impairs cAMP-gene regulation leading to the inhibition of chromatin remodeling, culminating in blockage of the transcription of genes that promote cell proliferation (Dang, 23 – 24).
Mutations in the Myc gene can lead to cancer in light of the crucial role that it plays in regulating cell proliferation. These mutations can transform Myc into an oncogene by restricting it to a state of permanent activation. Consequently, the CAC(G/A)TG E-box is permanently activated leading to constant transcription of cell proliferation-promoting genes. Therefore, mutations in Myc can cause cancer by locking the cell in a permanent state of cell division, pushing the cell cycle into overdrive (Dang, 30). Burkitt lymphoma is one form of cancer that underlines the significance of Myc mutations in carcinogenesis. Genetic analysis often reveals a translocation affecting Myc in tumor samples extracted from patients with this cancer. Unsurprisingly, one of the new frontiers of research in anticancer agents involves the development of agents that target Myc (Dang, 34).
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