Prof. Zvi Livneh

Our genetic material – DNA – is under constant assault. It is damaged every day by external forces like sunlight, radiation, tobacco smoke, air pollution, and food additives, and internal ones like waste products left over from the body’s metabolic processes.

“The DNA of each cell in your body is damaged about 50,000 times each day,” says Prof. Zvi Livneh. “That’s a massive attack.”

If left unrepaired, this damage can create disease-triggering mutations – including cancer. Fortunately, the body has a stock of enzymes whose job is to fix DNA. Upon detecting the damage, these enzymes go to work: they “operate” on the DNA, replacing the damaged parts with new ones. The efficiency of these repair enzymes is critical for preventing cancer.

“The DNA of each cell in your body is damaged about 50,000 times each day – and that is a conservative estimate,” says Prof. Zvi Livneh of the Weizmann Institute of Science’s Department of Biomolecular Sciences. Calculating the number of cells in the human body is tricky, but many estimates are in the trillions – and every single cell is assailed 50,000 times a day? As Prof. Livneh mildly puts it, “That’s a massive attack. 

“DNA repair is like molecular surgery to restore the original DNA sequence,” says Prof. Livneh, who has been studying the molecular mechanisms of DNA repair for three decades.

Most types of damage result in individual mutations – genetic “spelling errors” – that are corrected by precise, error-free repair enzymes. Sometimes, however, damage can cause gaps in the DNA, preventing the DNA molecule from being copied when the cell divides. The cell resorts to a sloppy but efficient repair technique to avoid these gaps: it fills in the missing DNA in an inaccurate fashion. This “error-prone” mechanism can save the cell from dying, but is a major source of mutations.

Prof. Livneh, collaborating with researchers in the U.S. and Germany, revealed how the error-prone repair works. The team found that it proceeds in two steps and requires two types of enzymes belonging to the family of enzymes called DNA polymerases, which synthesize DNA.

Our bodies have enzymes that go to work upon detecting DNA damage, replacing the damaged parts with new ones. 

First, one repair enzyme, “the inserter,” does its best to fit in a genetic “letter” into the gap, opposite the damaged site in the DNA molecule; several enzymes can perform this initial step, which often results in the insertion of an incorrect genetic letter. Next, another enzyme, “the extender,” helps restore regular copying of DNA by attaching additional DNA letters after the damaged site; only one repair enzyme is capable of performing this vital second step.

These findings may one day help make it possible to enhance DNA repair in people whose natural repair capabilities are deficient.

“We can use DNA repair in the battle against cancer – especially for cancer prevention,” says Prof. Livneh. “Since we know that individuals differ in their ability to repair DNA and that suboptimal DNA repair is a risk factor for cancer, we can find ways to assess who is most at risk.”

For example, he and Dr. Tamar Paz-Elizur, a researcher in his group, discovered that a weak DNA repair score, determined by measuring the activity of a panel of three DNA repair enzymes called OGG1, MPG, and APE1, is a strong risk factor for lung cancer. They then used this research to develop blood tests to assist physicians in the risk assessment and early detection of lung cancer.

One key way the tests could be used is to screen smokers and former smokers, identify those who are most at risk for developing lung cancer, and encourage them to quit smoking and seek early detection through proactive CT scans. Smoking contributes to 80 to 90 percent of lung cancer cases.

Prof. Livneh and his team developed a blood test that can assess a person’s risk of lung cancer, and now plan to devise similar tests for breast, colorectal, and pancreatic cancers.

Prof. Livneh explains that there were several reasons behind his decision to focus on lung cancer: it’s one of the most common cancers in the world, it’s the leading cause of cancer death, and early diagnosis can dramatically improve survival rates. Currently, only 16 percent of lung cancer cases are diagnosed at an early, more treatable stage. More than half of those with lung cancer die within one year of being diagnosed.

Clearly, early intervention makes a life-changing difference. That’s why Prof. Livneh next plans to develop blood tests that can help assess risk for breast, colorectal, and pancreatic cancers.

“The most effective way to deal with any disease, cancer included, is prevention,” he says, pointing to the example of how deaths from cardiovascular diseases have decreased due to widespread screening for biomarkers such as high cholesterol and high blood pressure.

Prof. Livneh hopes that, in the future, tests to measure DNA repair enzyme activity could have a significant impact on improving health. “We really believe that with this approach, you can reduce incidence of cancer,” he says. “That would be an amazing achievement.”

Prof. Zvi Livneh’s research is supported by the Swiss Society Institute for Cancer Prevention Research, which he heads; the Rising Tide Foundation; the Mike and Valeria Rosenbloom Foundation; Dana and Yossie Hollander; and the Comisaroff Family Trust. He is the incumbent of the Maxwell Ellis Professorial Chair of Biomedical Research.