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research paper on telomeres

The solution describes a research article testing the role of telomeres in cancer in mice.
These questions are specifically addressed:

(1) What is telomerase and what is it's role

(2) Phenotypes of p53 knockout in mouse and humans- how do they differ?

(3) Difference between carcinoma and sarcoma

(4) Breakage-fusion-bridge cycle of chromosome instability

Methods:

(1) Spectral karyotyping

(2) Survival curves (Kaplan-Meier plots)

Attachments

Solution Preview

(followup) I have attached the figure I referred to, as a powerpoint file.

I have tried to address your questions in comprehensive way, but please contact me if you need more detail.

(1) What is telomerase and what is it's role

Normally when cells undergo replication they lose repeat sequences of DNA from the ends of their chromosomes (telomeres). This limits the number of times a cell can divide, as when the telomeres become too short, the chromosomes become unstable leading to death of the cells. However if cells in culture are transfected with the telomerase gene, they can undergo an unlimited number of cell divisions. This is because telomerase prevents shortening of the telomeres by adding back DNA repeats, thereby stabilizing the chromosomes. Some cells which must undergo extensive cell division without becoming senescent, such as B or T lymphocytes, can upregulate telomerase. Similarly some tumor cells express telomerase, enabling them to continue to divide virtually indefinitely.

(2) Phenotypes of p53 knockout in mouse and humans- how do they differ?

The important thing to appreciate is that many human tumors have mutations inactivating p53, however most of these tumors are carcinomas. Mice genetically lacking p53 also develop tumors, but they are mostly sarcomas, a different type of tumor. It is not known why p53 deficiency results in different types of tumors in these two species. The reason why this paper is important is because it provides part of the answer. It indicates that for development of carcinomas, in addition to loss of p53, it is necessary to lose telomerase also, leading to chromosomal instability. Why this is necessary in carcinomas but not sarcomas is not understood, but presumably it is due to the different biology of epithelial cells vs connective tissue cells.

(3) Difference between carcinoma and sarcoma

Carcinomas are tumors derived from epithelial cells, whereas sarcomas are tumors derived from connective tissue cells such as bone, fat etc.

(4) Breakage-fusion-bridge cycle of chromosome instability

There is an excellent diagram explaining this process in Fig.1 of this reference:
http://www.nature.com/nrc/journal/v9/n3/full/nrc2591.html
if you cannot access it, let me know and I can email the figure to you.

In summary, a chromosomal break occurs that leads to the fusion of sister chromatids, forming a bridge between the two. This leads to a chromosome with two centromeres. During mitosis the aberrant forces on the chromosome that occur as a result of these two centromeres leads to breakage of the chromosome. ...

Solution Summary

This solution explains the experiments in a recent research paper (attached), regarding telomere function in cancer.

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