Are there known downsides to removing UV mutation hotspots to prevent some skin cancers (Genetic sunblock)?

Question

Khavari et al. recently demonstrated that a significant fraction of one of the major forms of skin cancer (cutaneous squamous cell carcinomas) are associated with a mutated KNSTRN gene (a protein associated with the kinetochore). They identify a specific region of the gene as being a hotspot for UV induced mutation and suggest that these mutations may be an early event in the development of this type of skin cancer.(1)Abstract from their nature paper (paywalled):>Here we report the discovery of recurrent mutations concentrated at an ultraviolet signature hotspot in KNSTRN, which encodes a kinetochore protein, in 19% of cutaneous squamous cell carcinomas (SCCs). Cancer-associated KNSTRN mutations, most notably those encoding p.Ser24Phe, disrupt chromatid cohesion in normal cells, occur in SCC precursors, correlate with increased aneuploidy in primary tumors and enhance tumorigenesis in vivo. These findings suggest a role for KNSTRN mutagenesis in SCC development.(2)My question:Scientists could theoretically alter the nucleotide sequence of the KNSTRN gene to remove the mutation hotspot, potentially lowering the incidence of this type of skin cancer. But are there any downsides to doing so? Are there any cases where a UV mutatable hotspot has shown to have some useful function in a cell or organism? Thanks!1. http://www.sciencedaily.com/releases/2014/09/140907181722.htm2. http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3091.html

Answer 1

This has been the "holy grail" for gene therapy--site specific alteration without adverse side reactions. Unfortunately, it has yet to be accomplished in humans. Using CRISPR technology, there has been some success in salamanders.

However, there has been a human death due to gene therapy. This resulted in an immediate halt via the regulating agency, the FDA. Therefore, in the studies you have been reading about the test systems have been cells harvested from a living cell line but grown in an in vitro (meaning outside of any living system--in a lab and contained in a lab tissue culture flask) or other tissue culture growth system. That's a whole new ballgame

That's the problem. As a formally-educated biophysical chemist who has worked with binding projects for gene therapy, I can tell you that what you can do in vitro is much easier than what you can accomplish in vivo (meaning inside a living organism). This is because you must have a reliable method to get your target to the desired location and it must bind speciificly so as not to bind somewhere wrong to cause DNA replication errors there--causing loss of vital protein products (which was the cause of the human gene therapy death).

Usually the target has an attached moiety that is active to facilitate the desired reaction (CRISPR) in this case. In cancer research, a targeting sequence with an attached dye has been used. In other research, a peptide oligomer has been used as a targeting sequence to which is attached the drug of choice. However, in my research, I found oligonucleotides to be more suitable.

Nevertheless, say all the binding issues, all the solubilities issues, all the toxicity issues were worked out and the targeting "link" and its corresponding "active drug" were able to specifically bind to the desired mutation site on the mutated DNA so as to repair the mutation, would there be an adverse reaction to repairing a mutation? No, the body has it's own repair mechanisms and they usually work on their own. However, when the damage is too massive, they fail and that's when cancer shows up.

The only bad thing you can do is place a targeting tag with an active agent to repair a desired mutation and it binds to the incorrect DNA sequence and messes that sequence up so that all products that eventually come from it are waste bc the body cannot use them or the DNA sequence that is altered is critical to regulating that entire gene and all its products or metabolism meaning that now it has the potential to be a cancerous producing DNA sequence. In the case of the human death, essential proteins were no longer able to be produced by that human body because the target sequence did not bind specifically. It bound to most of the DNA coding for proteins essential for basic protein products needed for metabolism, cell structure, life etc.

I hope this answers your question or gives you food for thought!!!