Westlake News PEOPLE

Ask an Expert: How Does DNA Damage Cause Cancer?

Jocelyn Eikenburg
23, 2022

Email: zhangchi@westlake.edu.cn
Phone: +86-(0)571-86886861
Office of Public Affairs

Damage to the DNA in our cells has long been recognized as a fundamental cause of cancer. But how exactly does DNA damage lead to cancer, and what can we do to reduce the risk?

Prof. Xiaochun Yu, who heads the Genomic Instability and Tumorigenesis Laboratory at Westlake and previously was a full professor at the University of Michigan Medical School, has extensively researched DNA damage response mechanisms and their role in the development of tumors. We asked him to explain more about the link between DNA damage and cancer, as well as novel treatment approaches and prevention.

What is DNA damage?

As you know, DNA is the genetic material for our lives. However, DNA can be easily damaged by many environmental hazards and internal hazards. Environmental hazards include UV ionizing radiation and many types of chemicals. Internal hazards include free radicals generated during cell metabolism. These hazards can induce many types of DNA lesions, such as single-stranded breaks and double-stranded breaks. If these breaks are not properly repaired, the lesions will accumulate and eventually induce tumorigenesis (the formation of tumors).

Could you talk a little about the mechanisms behind DNA damage and how that can lead to cancer?

So basically, the lesions, if not repaired, are transmitted from mother cells to daughter cells during cell division, and also if the lesions are not repaired during the DNA replication, one lesion will replicate into two lesions. That's how lesions will accumulate in cell populations. So you will see a group of cells which will have similar types of lesions and one will eventually accumulate over the threshold and induce tumorigenesis.

If you look at cancer, it is a chronic disease. Basically, the lesions accumulate for years and eventually are over the threshold, which leads to the transformation of normal cells into tumor cells. That means cell growth without any limitation.

So what can prevent this from happening?

Through the process of evolution, we have a kind of DNA damage response system. We can call it a temporary repair system as a whole. Basically, the cells will sense those lesions and will send the repair machinery to the DNA to fix those lesions. This is a defense system for ourselves. However, during cell growth, there are always some spontaneous mutations which could occur and once the mutations occur, sometimes they may mess up the DNA damage repair system. And if the mutation causes a repair deficiency, that will induce accumulation of the lesions.

Actually, these repair factors are important tumor suppressors. Any mutations on these repair factors will induce lesion accumulation and then eventually cause cancer.

Our studies basically look at the molecular mechanism behind how these genetic mutations abolish the DNA repair and therefore induce tumorigenesis. And once we have studied all these mechanisms, we have to think about methods to treat cancer.

What are some novel treatment methods for cancer which you've been researching?

We are using a very interesting strategy to treat cancer.

As I just explained, tumor cells may have a repair deficiency. That means once the DNA damage occurs, the tumor cells have some partially abolished repair ability. Therefore, if we give the tumor cells a certain level of damage agent treatment, we will induce additional damage that tumor cells cannot handle, but normal cells can handle. Therefore, that can specifically kill the tumor cells but also not harm normal cells.

The typical example is chemotherapeutic drugs. Chemotherapeutic drugs basically are DNA damaging agents that induce different types of DNA lesions that can selectively kill the tumor cells. However, the chemo drugs basically have other side effects, and they are also very harmful to normal cells.

Over the past 20 years, the US Food and Drug Administration and other agencies basically try to identify alternative methods to treat cancer. We call targeted therapy a new era of drug development.

Right now we are utilizing one exciting strategy -- we call it the synthetic lethality approach.

So to give you a basic introduction, in normal cells, imagine that DNA damage repair is much like a human with two hands. If a lesion occurs, the cells use these two hands to repair the damage. However, in the tumor cells, because of genetic mutations, you lose a hand, so there is only one hand to barely fix the lesions. However, it cannot totally fix the lesions and the regional accumulation will cause transformation of the cell and cause tumorigenesis.  

In this synthetic lethality approach, if we specially target that one hand, then the tumor cell does not have any hands, and the tumor cell will die. In normal cells, if we just cut one hand, you still have another hand to repair the DNA. So normal cells will not be killed by this strategy.

What can we do to reduce the risk of DNA damage and thus cancer?

There are many types of lesions induced by free radicals generated during our metabolism. Therefore we use antioxidants that can kill all these free radicals. For example, if we eat more vitamin C or vitamin E that will absolutely reduce free radical levels. It's one of the strategies for tumor prevention, which can lead us to have longer and healthier lives.