A new specific cancer target?

New cancer treatments are needed to replace many of the current treatments that have toxic side effects. Targeting cancer cells is very difficult to do without also damaging healthy cells, however we may be able to do just that by using the cancer’s own tricks against it. A specific cancer treatment could be produced if the link between the base excision repair and unfolded protein response pathways could be exploited.

DNA is vital for the survival of cells by coding for proteins that the cells need. Proteins are produced from DNA in two processes called transcription, where DNA is used as a template to make RNA, and translation, where RNA is used as a template to make a protein. However, it may surprise you to know that DNA is damaged up to 10,000 times per cell per day. This damage will affect the production of the proteins that DNA encodes.

When proteins are produced, they fold into a 3-dimensional structure, but DNA damage leads to the production of proteins that do not fold correctly. This can then trigger a stress pathway called the unfolded protein response. This aims to clear misfolded proteins, but if there’s too much misfolded protein, and therefore too much DNA damage, this pathway will trigger the cell to die. We have evolved to have several mechanisms like this where cells will die if their DNA is damaged beyond repair to avoid producing mutations that could eventually lead to cancer.

This pathway is interesting because our research has shown that there is a link between base excision repair and the unfolded protein response, such that the unfolded protein response will not be activated in the absence of base excision repair following damage by alkylating agents. Without the unfolded protein response, cells may not die when they have sustained DNA damage which allows mutations to occur.

So why does this matter? We know that some types of cancer like to reduce DNA repair which allows them to pick up mutations faster. We also know that cancer cells love to avoid dying. Both of these things allow cancers to progress and become more serious. However, this link between base excision repair and the unfolded protein response covers both of those problems.

If the link between these two pathways could be switched on this could specifically trigger cell death in cancer cells via the unfolded protein response, allowing them to be killed without killing healthy cells that do not have damaged DNA. Treatments like this are very important to replace many of the current treatments that have toxic side effects.

On the flipside, the link between these pathways could be switched off to protect cells from dying. This would be useful for diseases associated with misfolded proteins. This includes Alzheimer’s disease, potentially reducing the loss of neuronal cells in the brain.

We do not yet understand how the two pathways are linked, but with further research this could be determined, allowing us to target it.

Further reading:

1. Transcription. BBC Bitesize. (2021), BBC. Available at: https://www.bbc.co.uk/bitesize/guides/zvsmd6f/revision/6 (Accessed: 01/01/2021)

2. Translation. BBC Bitesize. (2021), BBC. Available at: https://www.bbc.co.uk/bitesize/guides/zvsmd6f/revision/7 (Accessed: 01/01/2021)

3. What is Cancer? BBC Bitesize. (2021), BBC. Available at: https://www.bbc.co.uk/bitesize/guides/z324fcw/revision/2 (Accessed: 01/01/2021)

4. Aag-initiated base excision repair drives alkylation-induced retinal degeneration in mice. Meira, L. B., Moroski-Erkul, C. A., Green, S. L., Calvo, J. A., Bronson, R. T., Shah, D., & Samson, L. D. (2009). Proceedings of the National Academy of Sciences of the United States of America, 106(3), 888–893. https://doi.org/10.1073/pnas.0807030106

5. Aag DNA glycosylase promotes alkylation-induced tissue damage mediated by Parp1. Calvo, J. A., Moroski-Erkul, C. A., Lake, A., Eichinger, L. W., Shah, D., Jhun, I., Limsirichai, P., Bronson, R. T., Christiani, D. C., Meira, L. B., & Samson, L. D. (2013). PLoS genetics, 9(4), e1003413. https://doi.org/10.1371/journal.pgen.1003413

6. Targeting the unfolded protein response in disease. Hetz, C. Chevet, E. Harding, H. (2013), Nature reviews, 12, 703–719. Available at https://www.nature.com/articles/nrd3976 (Accessed: 26/02/2020)