Correcting DNA mistakes

Using the knowledge of how the cell repair systems work will open the door to more effective cancer treatments



UNDERSTANDING how our cells repair damaged DNA, a breakthrough which earned the Nobel Chemistry Prize recently, could make cancer treatment more effective, experts say.

By revealing how our cells automatically fix DNA mutations which can lead to illness, the discovery opened the door to significantly improving chemotherapy’s effectiveness against cancer, which kills some eight million people worldwide each year.

“You can use this knowledge to destroy cancer,” said Nora Goosen, a DNA repair expert at Leiden University in the Netherlands.

Chemotherapy attacks cancer cells by trying to scramble their genetic code and thus their ability to multiply, but cancer cells, just like healthy ones, do not give up without a fight.

he cell repair systems are going to try to undo the work of doctors by fixing the damage the doctors were trying to inflict,” said Terence Strick, a DNA repair researcher at the Jacques Monod Institute in Paris.

One solution would be to inhibit the ability of cancerous cells to self-mend.

“If you attack these repair mechanisms (in cancer cells) in combination with chemotherapy and other drugs ... it (treatment) can be more effective,” Goosen said.

Sweden’s Tomas Lindahl, Paul Modrich of the United States and Turkish-American Aziz Sancar were awarded the top chemistry award for unravelling the process by which our cells repair mutations caused to DNA by the Sun or carcinogenic substances found in alcohol and cigarettes, for example.

Mistakes in DNA, the chemical code for making and sustaining life, can cause cells to malfunction, age prematurely, and become cancerous.

The vast majority of changes to our DNA are immediately corrected, but some accumulate and lead to cancer. Some people are more susceptible to cancer because their DNA repair response is faulty.

Ironically, the same repair mechanism identified by the Nobel laureates can also cause cancerous cells to resist the effects of cancer treatment.

Alan Worsley, a spokesman for the charity Cancer Research UK, said new drugs are being developed to fight the disease.

He cited the treatment olaparib, which stops cancer cells from fixing DNA damage. It was approved by the European Commission in December 2014 for use in Europe.

Alain Sarasin of France’s CNRS research institute highlighted the risks of interfering with DNA repair systems.

“We don’t yet know how to target tumour cells specifically. If we gave a patient a molecule which inhibits the self-repair mechanism of cancer cells, it may also inhibit the repair systems of other cells like white blood cells,” he said.

“If, one day, we have a molecule which reinforces the DNA repair and can be targeted to blood cells, for example, followed by chemotherapy after, this would allow us to increase the chemotherapy dosage without unintentionally killing blood cells.

“For now, we don’t know how to do that.” – AFP

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Discovery of DNA Repair Methods Nails 2015 Chemistry Nobel Prize

Three scientists who found ways that cells fix damaged DNA—staving off cancer and other diseases—have won this year's prize

There are three reasons we are not constantly riddled with cancer, and today the scientists who discovered those reasons—three ways that cells repair damaged DNA that can ruin bodies--won the 2015 Nobel Prize for Chemistry.

This morning The Royal Swedish Academy of Sciences announced the coveted prize is going to Tomas Lindahl from the Francis Crick Institute and Clare Hall Laboratory in Hertfordshire, England; Paul Modrich from the Howard Hughes Medical Institute and Duke University School of Medicine in North Carolina in the United States; and Aziz Sancar from the University of North Carolina in Chapel Hill, also in the U.S. “I know, over the years, that I’d been mentioned for the prize,” Lindahl said in a telephone call to the academy. “But hundreds of people get considered every year so I feel very lucky.”

He and the other two researchers, working independently over the last 40 years, described three different mechanisms that create errors in DNA—the molecule that controls cell behavior—and the different ways that chemical and biological processes fix many of these problems.

“All forms of cancer start with DNA damage,” said biochemist Claes Gustafsson, one member of the Nobel chemistry committee. “If you do not have DNA repair, we would have a lot more cancer. That’s how important this is.” He added that the repair techniques let us understand how cigarette smoke, sunlight, and even mundane substances like water can damage DNA and point to ways that the damage can be rectified.

It is not just about cancer, Diane Grob Schmidt, president of the American Chemical Society, told Scientific American in an interview. “The understanding that we have of these mechanisms help us design drugs to repair all sorts of DNA errors,” she said. There are also several genetic diseases caused by the inability of cells to fix DNA properly, for instance, and work on the repair methods aids understanding of these ailments and how to treat them.

The discoveries illustrate the crucial and central role of chemistry, Schmidt added. “These mechanisms are fundamentally about the making and breaking of chemical bonds,” she said.

Scientists used to believe that DNA molecules were extremely stable. After all, they had to reliably transmit genetic information from generation down to generation. Then in the 1970s Lindahl demonstrated that the neat double helix and its components constantly decays. Every day, hundreds of those components, the DNA building block chemicals abbreviated as A, T, C, and G, get knocked out of their places. If the process continued unabated, the development of life on Earth would have been impossible. This insight led Lindahl to discover a series of enzymes and reactions, called base excision repair, which constantly works to fight this decay. The C building block, for instance, is repeatedly broken down into another molecule that should not be in DNA. The enzymes Lindahl found identify that broken molecule and rebuild it into a C.

Sancar found that cells use another technique to repair damage to DNA caused by ultraviolet light, the same thing that gives you a sunburn. This DNA fix is called nucleotide excision repair. People born with defects in this repair system will develop skin cancer if they are exposed to sunlight. Excision enzymes cut out the DNA lesions. The cell also uses this repair system to correct DNA damage people get after they are born, when they encounter mutagenic substances

Finally, Modrich found out how a cell corrects errors that occur during a vital biological process: Cell division, when DNA is replicated. This copying process is supposed to produce identical strands of DNA but often there are stretches of the new stand that do not match up. The set of cellular chemicals that Modrich found, a complex called mismatch repair, scans the strands and fixes them, reducing the error frequency during replication by about a thousand times during each replication cycle. (Modrich co-authored a Scientific American article on genetic engineering.)

“Without all of these repair mechanisms.” Lindahl said, “we would not be long-lived.” For finding them, he and the two other scientists will split $1 million dollars in three equal shares.
- By Josh Fischman | Scientific American







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