DNA Repair as a Double-edged Sword in Cancer

Helloo,

It’s Nil, your favourite Cancer Research Project student at the University of Surrey. In my first blog, I gave you an overview of my supervisor’s (Dr. Lisi Meira) work in the Cancer Research Field and what’s ahead of us in the second semester with this specific project that I am undertaking. Just a reminder, my colleague Tom and I will be looking at alkylation-induced damage and the corresponding stress response in both cancer and healthy cells. In order not to overwhelm you, I didn’t dive into the specifics last time, however, now, it is time to get serious about cancer. 

But first, what is cancer?  

The structure of DNA – a double helix.  
Image: Caroline Davis2010 (CC-BY)

Every cell in our bodies has DNA, which is short for deoxyribonucleic acid. DNA is the genetic code, which carries the instructions for the development, functioning, growth and reproduction of all cells and organisms. The way that cancer cells develops is by the acquisition of a number of changes, which we call mutations, in the DNA. These mutations are a consequence of DNA damage. DNA damage is not one in a million chance event; actually, it’s quite the opposite. Due to the continuous interaction of our DNA with reactive agents abundantly present both in the external environment and our internal environment (inside our cells!), DNA damage is inevitable For the effects of the acquired mutations in the DNA, see table below.

This table adapted from
http://sphweb.bumc.bu.edu/otlt/MPH-Modules/PH/PH709_Cancer/PH709_Cancer7.html
shows the characteristics of cancer cells. The comparison with normal, healthy cells and the histochemistry images enhance the understanding of the DNA mutations acquired and their result on a cellular level.

 

Most cancer therapies rely on inducing DNA damage in order to kill cancer cells. In cancer treatments, one of the most commonly used group of drugs is called alkylating agents. 

So, how do alkylating agents work?

DNA is a double helix molecule. It’s made up of repeating units called nucleotides. Each nucleotide contains a sugar and a phosphate molecule, which make up the ‘backbone’ of DNA, and, one of four organic bases. The bases are adenine (A), guanine (G), cytosine (C) and thymine (T). (Gamble, 2019). Alkylating agents work by adding an alkyl group to the guanine base of the DNA molecule, preventing the strands of the double helix from linking as they should. This causes breakage of the DNA strands, affecting the ability of the cancer cell to multiply. Eventually, the cancer cell dies (Drugs.com, 2019).

How is DNA damage dealt with?

Our bodies are capable of dealing with DNA damage by a complex set of mechanisms, which are collectively known as DNA repair. When looking at cancer, DNA repair is a double-edged sword; in healthy cells, it will decrease the chance of accumulation of mutations and the transformation into a cancer cell, but once cancer has developed, DNA repair may contribute to cancer’s resistance to chemotherapy. Dr Lisi Meira’s lab pioneered work characterising one of the DNA repair enzymes, namely alkyladenine DNA glycosylase (AAG). Their work revealed the importance of AAG in cancer induction and treatment. One unexpected finding of their work was how AAG coordinates with other cellular stress mechanisms, specifically those associated with endoplasmic reticulum (ER) stress and protein damage or misfolding. I know that I went from explaining everything from the start in really simple baby steps to bombarding you with all new terminology, but just keep reading for now, please. Everything will come together in the end.

So what?

The importance of our research comes into play when thinking about the impact the new findings about AAG could have. As a first step, Dr Lisi Meira and her team have shown the critical role that AAG plays in cellular stress responses and the pathology of cancer. Do these pathways link together? And if so, how do they link? We have considered AAG among other enzymes to act upon their canonical functions. Now, it is time to consider the non-canonical functions of AAG. At the end of our research, our findings and the new understandings can impact not only cancer treatment areas but neurodegeneration research as well.

Hopefully, by the end of this blog post you have learned essentially what cancer is and which chemotherapy compounds are most commonly used in cancer treatment. Another goal of mine with this post was to establish the link between alkylating agents and my current project. With the knowledge that you have just gained, I’m hoping that currently you are wondering about the DNA repair mechanisms, which are concerned with alkylation-induced damage and the ER stress response, because that is exactly what I am going to be writing about in my next blog post!

Take care,

Nil

Bibliography:

Gamble, Z. (2019). What is DNA? –. [online] science made simple. Available at: http://www.sciencemadesimple.co.uk/curriculum-blogs/biology-blogs/what-is-dna [Accessed 28 Nov. 2019].

Kufe, D., Pollock, R. and Weichselbaum, R. (2003). Holland-Frei Cancer Medicine. 6th ed. Decker Periodicals Publ Inc. 

Drugs.com. (2019). List of Alkylating agents – Drugs.com. [online] Available at: https://www.drugs.com/drug-class/alkylating-agents.html.