Question

In: Biology

BRCA1 and BRCA2 proteins have many roles within a cell. Although their primary role is in...

BRCA1 and BRCA2 proteins have many roles within a cell. Although their primary role is in DNA repair, they are also involved in halting the cell cycle upon detection of damaged DNA, utilizing cell cycle checkpoints. BRCA proteins are also able to activate cell death if the DNA damage is too extensive for repair. Therefore, BRCA proteins are essential for maintaining the stability of our genome, and without them we are at increased risk for cancer. Consider what would happen in the following context:

BRCA1 mutant cancer cells were observed to have shorter telomeres and increased sensitivity to telomerase inhibition, compared to cell lines with wild-type BRCA1. In fact, BRCA1 mutation carriers and breast cancer patients showed the shortest average telomere lengths compared to healthy patients suggesting that BRCA1 plays an unexpected and important function in telomere maintenance. Frankenstein01 is a telomerase inhibitor that is currently in clinical trials for the treatment of cancer. Given what you know about the normal function of BRCA1 and the roles of telomeres for genome stability:

A. Would you expect Frankenstein01 treatment to have enhanced anti-cancer activity (aka growth-inhibiting or killing activity) in BRCA1 mutant breast/ovarian cancer cell lines compared to wild-type cancer cells? Please explain briefly.

B. Would you expect Frankenstein01 treatment to have additive effects with DNA-damaging drugs that induce double strand DNA breaks in BRCA1 loss of function mutant (-/-) cancer cells compared to cancer cells with normal BRCA1 (+/+)? Why or why not?

Solutions

Expert Solution

A.

            Telomeres have been proposed to act as a ‘mitotic clock’ that counts the number of divisions a cell has undergone and its capacity for continued division. Normal cells have a finite replicative capacity in vitro after which they remain metabolically active but cease to proliferate. This period of growth arrest is referred to as M1 (mortality 1) or cellular senescence. A direct relationship between telomere length and cellular senescence has been established. Because of the end-replication problem, 50-200 bp of telomeric DNA is lost with every round of replication. The non-coding telomeric repeats provide a buffer that prevents the loss of genetic information during each cycle of replication. When the telomeres have eroded to a critical minimum length (∼5 kb), cellular senescence is triggered. Cellular senescence might be bypassed by repression of tumor suppressor genes, activation of oncogenes, or other mutations. By escaping senescence, rare cells continue to divide and their telomeres continue to shorten until they reach a critical stage (M2 or crisis). At this point, chromosomal instability arises due to end-to-end fusions and/or chromosome breakage. DNA damage checkpoints are activated along with apoptosis. Unless the cell develops a mechanism through which to stabilize telomere length, it will not survive. Cells that escape crisis and become immortalized generally achieve telomeric stability through the reactivation of telomerase

            The widespread expression of telomerase in a variety of human cancers, while being almost undetectable in most normal cells, makes it a very attractive drug target. Normal somatic cells are thought to harbor enough telomeric DNA reserve to withstand telomere-based therapeutics, and the few normal cells which express telomerase should also have enough reserve to withstand treatment with telomerase inhibitors. It has been shown that cancer cells often maintain much shorter telomeres than normal cells (3-9 kb compared to 10-15 kb). Additionally, the rapid proliferative nature of cancer cells leads to steady telomere erosion in the absence of telomerase. Thus frankestein 01 telomerase-based therapeutics should therefore impact tumor cells before having any appreciable effect on telomerase-positive normal cells.

B.

            No, telomerase inhibitory drugs might not have additive effects with DNA damaging drugs. Because telomerase inhibitor will inhibit the telomerase’s activity to induce cell senescence or/and apoptosis. This will act as a target drug. On the other hand DNA damaging drugs are generally not target specific and have side effects e.g. Chemotherapy


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