Chromosomal Instability - Essay Example

Chromosomal Instability Chromosomal instability (CIN) is a causal factor in cancer, because it results in aberrations in the normal mechanisms for replication of cells. While chromosomal instability is acknowledged to be a factor that contributes to the development of tumors, there is an inadequate understanding of the underlying molecular mechanisms that can cause chromosomal instability. The results and findings of some recent research studies on the subject of chromosomal instability are detailed below. One of the hallmarks of cancer is underlying genomic instability, where due to the aberrations in the genomes, there is chromosomal instability leading to aneuploidy, i.e, an imbalance in the chromosomes results, so that the possibility for cancerous growths is increased.(Pollack, 2006). In a brief article, Pollack (2006) has summarized the findings of a study of aneuploidy that was taken up recently, where a gene expression was identified as a possible identifying symptom of chromosomal instability. In their study of chromosomal instability, the authors identified 25 genes that could predict the clinical outcome for six different types of cancer. Maintaining the chromosomal integrity of a cell is a complicated process because DNA regulation in the cell must be precisely regulated, while damaged DNA must be recognized and repaired quickly. Shima et al (2007) conducted earlier studies where they identified a Chaos3 mutation in mice that causes spontaneous chromosomal aberrations. In the instant study, they report that this chromosomal instability, which was isolated in a forward genetic screen, is a viable allele of Mcm4 (michromosome maintenance deficient 4 homolog). This allele is a component of the MCM2-7 complex, which is the replication licensing factor. Shima et al (2007) conducted their study on female mice and found that mutant embryonic fibroblasts in these mice were susceptible to chromosomal instability induced by inhibition of DNA replication. 80% of the subjects of the study succumbed to mammary carcinomas. The findings in this study suggest that the hyphomorphic alleles such as mcm4 of the genes that encode the subunits of the MCM2-7 complex may cause an increase in the risk of breast cancer. Another causal element identified in chromosomal instability is the mSds3 chromatin regulator, which is a key component of the mSin3 compressor complex that regulates target gene expression through chromatin modification.(David et al, 2006). In their study, David et al (2006) carried out their study using mice assessed whether the loss of one copy of mSds3, either alone or in combination with a p53 mutation results in aneuploidy or a tendency to develop cancer. The authors observed that in the absence of p53, the loss of mSds3 increases chromosamal instability and accelerates tumorous growth. But the presence of even one unit of p53 works to suppress the development of tumors, suggesting that p53 plays a role in association with mSds3 in monitoring mitotic fidelity. The authors have concluded that the capacity of mSds3 to cooperate with deficiency of p53 where there is a predisposition to cancer, is related to its specific role in chromosome segregation. Chromosomal instability (CIN) can cause chromosomal rearrangements, which can include changes in chromosome number to facilitate tumorigenesis. Akio et al (2007) have built upon the results of previous research, which has suggested that activation of the canonical Wnt signal pathway can induce transcription of a new set of genes through the T cell factor, which in turn regulates cell multiplication and differentiation. Akio et al (2007) have shown that Wnt signaling brought on through mutations of the Adenomatous Polyposis Coli (APC) gene can also be a causal factor in chromosomal instability. In their study, the authors used mouse polyps and ES cells, in which Wnt signaling was activated through APC or Beta Catenin gene mutations. Their findings in the study suggested that Wnt signaling caused higher rates of aberration in chromosomes, and they have concluded that TCF or Beta-Catenin mediated transcription may itself be a factor in increasing chromosomal instability by interfering with G2/M progression. A study conducted by Boglioli et al (2007) have specifically examined chromosomal instability in relation to Fanconi Anemia, a disease that is characterized by failure of the bone marrow, which consequently leads to a susceptibility to cancer. In their study, these authors deliberately induced DNA damage to human and MRC5 fibroblasts by subjecting them to local irradiation, which caused interference in the cell replication function. In their study, the authors have examined the role of the FA/BRCA pathway, because the FA pathway is a central node in the network of chromosomal instability and tumor suppression. They focused their study on the functional requirements of FANCD2, which is a key protein in the FA pathway. The irradiation of fibroblasts of different cultures and different genetic backgrounds caused stalled replication forks along this pathway, and at different times after the irradiation process, the relocation of FANCD2 and other proteins to the site of damage was measured. Boglioli et al (2007) have also examined the existing belief that the histone H2AX is strictly required to send the protein FANCD2 to the site of damage. The authors have discussed the controversies concerning the role of H2AX in genome stability. On the one hand is the acknowledgement that H2AXmay be essential for the deployment of the DNA damage response proteins to the site of the damage. On the other hand is the recognition that it is not required for the initial recognition of DNA impairment, which suggests that it is more likely to be involved in the retention of repair factors rather than in actual recruitment. Based upon their study Boglioli et al (2007) have developed a model based upon the data reported in their study as well as other studies. Irradiation induces DNA lesions which block the cell replication forks. This activates ATR which then phosphorylates both FANCD2 and H2AX. The phosphorylated H2AX then allows the recruitment of FANCD2 to the site where the replication forks are stalled and the DNA lesions are repaired. After this repair occurs, there is no further signal for activation of ATR and the FA pathway is inactivated. The authors found that FANCD2 is normally also activated in the absence of H2AX, thereby offering the possibility that it may not strictly be required for the dispatch of FANCD2 to the site of DNA damage. When DNA damage is generated within a cell, the conserved protein kinase Chk1 mediates the cell cycle progression. In a study conducted by Ahmed et al (2007), Msc1 was identified as the multicopy suppressor that enables cells to survive and a loss of function of this component causes chromosome loss and promotes chromosomal instability. These authors examined the function of Msc1 using the yeast Schizosaccharomyces pombe, which has been found to be a useful model for studies of cell cycle events. When DNA damage occurs, caused by irradiation or any form of aberrent DNA replication, then the activity of cyclindependent kinases is inhibited. This in turn causes the phosphorylation of the protein kinase Chk1, which inhibits mitotic entry. Ahmed et al (2007) found that a fission yeast protein Msc1 is the agent responsible for suppressing chromosomal instability in cells that are defective in Chk1 functions. While cells in which Msc1 is lacking are relatively resistent to DNA damage, a loss of Msc1 causes increased DNA damage, which is the direct result of the loss on Chk1 funciton. The DNA damage results in chromosomal instability. Ahmed et al (2007) in their study, have tried to show that Msc1 is necessary for the stability of chromosomes. Msc1 carries out ts function using the histone H2A variant of H2A Z, which is encoded by pht1 in yeast. Hence in order to suppress DNA damage and restore chromosomal stability, multicopy Msc1 presence is required, as also pht1. Ahmed et al (2007) have presented evidence to show that the histone H2A.Z may be a partiicpant in centromere function in yeast and may help to promote chromosomal stability after DNA damage has occurred. This study is an important one, because it serves to identify the components of the cell that could play a role in improving chromosomal stability and restoring it after DNA damage has occurred. Penserga and Skorski (2007) have examined the role of fusion tyrosine kinases in the repair of aberrations arising due to chromosomal instability. When spontaneous DNA breaks occur and there is unfaithful repair of these breaks due to conditions such as ocidative stress, radiaiton, replication stres or toxic chemicals, then reciprocal chromosomal translocations may arise. Specific kinds of chromosomal rearrangements are asociated with certain cancers and can provide a means for diagnosis of cancers. Fusion tyrosine kinases (FTK) are an important part of such an identificatiopn proces, because genes encoding thes tyrosine kinases are targeted by the chromosomal translocations and result in the generation of chimera. Penserga and Skorski (2007) have shown that FTKs can help in facilitaing the repair of DNA and due to their kinase constituent element, they are able to show transforming activity. But the therapeutic value of FTKs may be limited because they can also compromise the fidelity of the repair mechanisms and this may lead to more genetic abnormalities caused by higher levels of chromosomal instability. Thes FTK’s also increaes the level of expression of antiapoptotic protein Bcl-XL and this makes it more difficult to provide treatment in the case of those cells which are infected with tumors. Although chromosomal instability is acknowledged to be one of the salient factors influencing the development of tumors, the molecular mechanisms underlying this phenomenon are generally poorly understood. (Carter et al, 2006). 18 gene expresion data sets of various cancer types in human beings were examined by Carter et al (2006), who found that a high tFA predicted a poor clinical outcome where caner was concerned. These authors developed a computaional method by which they were able to characterize aneuploidy in cancerous cells based upon the gene expresions in localized chromosomal regions. They determined the total levels of chromosomal aberation in each tumor. Based upon specific genes expresion, thes authors were able to derive a signature of chromosomal instability, because such expresion was consistently asociated with aneuploidy. These authors also found that the signature identifying chromosomal instabiltiy was higher in metastasis samples as opposed to primary tumors. This is also an important study because it provides for a wat to asses chromosomal instability and thereby detremine the extent of malignancy that could potentially impact a wide range of tumors. On the basis of the above, it may be concluded that the studies have shown the possibiltiy that certain components of cells may contribute to chromosomal instability through their actions. One of these is the hyphomorphic allele mcm4, another is through APC or Beta Catenin gene mutations, and yet another causal factor could be through an irregularity in the mSds3 chromatin regulator. The studies above have also identified cell elements that can contribute to lowering chromosomal instability by facilitating of DNA abnormalities. One of these is FANCD2, which is a key protein in the FA pathway. Another is the presence of the multicopy Msc1 protein. Fusion tyrosine kinases (FTK) may contribute to the deteciton of cancer, but may not be helpful in facilitating repair of tumorous cells because thye can compromise the fidelity of repair mechanisms. In the case of human cells demonstrating chromosomal instabiltiy and theherby showing the prersence of tumors, high tFA levels can predict a poor clinical outcome. References: * Ahmed, Shakil, Dul, Barbara, Qiu Xinxing and Walworth, Nancy C, 2007. “Msc1 acts through histone H2A.Z to promote chromosome stability in Schizosaccaromyces pombe”, Genetics, 177(3): 1487-1498 * Aoki, K, Aoki, M, Sugai, M, Harada, N, Miyoshi, H, Tsukamoto, T, Misoshita, T, Tatematsu, M, Seno, H, Chiba, T, Oshima, M, Hsieh, C-L, and Taketo, M.M, 2007. “Chromosomal instability by Beta-Catenin/TCF transcription in APC or Beta-Catenin mutant cells”, Oncogene, 26:3511-3520 * Bogliolo, Massimo, Lyakhovich, Alex, Callen, Else, Castella, Maria, Cappelli, Enrico, Ramirez, Maria J, Creus, Amadeu, Marcos, Ricard, Kalb, Reinhard, Neveling, Kornelia, Schindler, Detlev and Suralles, Jordi, 2007. “Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability”, The EMBO Journal, 26: 1340-1351 * Carter, Scott L, Eklund, Aron C, Kohane, Isaac S, Harris, Lyndsay N and Szallasi, Zoltan, 2006. “A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers”, Nature Genetics, 38(9): 1043-1050. * David, G, Dannenberg, J-H., Simpson, N, Finnerty, P.M., Miao, L, Turner, G.M., Ding, A. Carraso, R and DePinho, R.A., 2006. “Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53”, Oncogene, 25 :7354-7360 * Penserga, ETP and Skorski, T, 2007. “Fusion tyrosine kinases: a result and cause of genomic instability”, Oncogene, 26:11-20 * Pollack, Jonathan R, 2006. “Chromosome instability leaves its mark”, Nature Genetics, 38(90: 973-976 * Shima, Naoko, Alcarez, Ana, Liachko, Ivan, Buske, Tavanna R, Andrews, Catherine A, Munroe, Robert J, Hartford, Suzanne A, Tye, Bik K and Schimenti, John C, 2007. “A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice”, Nature Genetics, 39(1): 93-100 Read More