Nobel Prize in Chemistry 2015: The Tool Box for DNA Repair

 

“This year’s prize is about the cell’s tool box for repairing DNA and safeguard the genetic information,” Göran Hansson explained in Stockholm today. Hannson is the secretary general of the Royal Swedish Academy of Sciences. He continued by explaining that each person’s DNA, the sum of all genetic information stored in his or her chromosomes, is constantly changing and degrading, due to radiation, replication errors or damaging substances. Without specialised molecular systems that monitor and repair it constantly, our DNA would break down so quickly that ultimately, no human life could possibly be sustained on Earth.

Nowadays, molecular biology knows three distinct DNA repair mechanisms, and each can be linked to a specific scientist who discovered it – and each of them received a share of today’s Nobel Prize: Lindahl for ‘base excision repair’, Sancar for ‘nucleotide excision repair’, and Modrich for ‘mismatch repair’ respectively.

Tomas Lindahl: Base excision repair
In the late 1960s, when molecular biology was still excited about the discovery of the DNA double helix, and this form and packaging of DNA was considered to be extremely resilient, the young Swedish researcher Tomas Lindahl had his doubts. As a postdoc at Princeton University, he had discovered that RNA was actually quite unstable. Years later, when he was back in Sweden at the Karolinska Institutet, he could prove that DNA was unstable as well – and began searching for repair mechanisms in bacteria. He found a repair mechanism that he called ‘base excision repair‘ that constantly monitors and repairs smaller DNA damages. He also discovered unkown enzymes,  DNA glycosylases, that are the “tools” of this constant repair process.

 

 

Today Tomas Lindahl was interviewed via telephone during the Nobel committee press conference. He explained that DNA repair can be seen as “a double-edged sword”: If DNA can be repaired in healthy cells, even cancer cells are able to repair their own DNA and thus counteract all kinds of cancer treatment. After his groundbreaking discoveries, Lindahl specialised in cancer research and moved to the United Kingdom in 1981, to work at what is now Cancer Research UK. He is emeritus director of Cancer Research UK at Clare Hall Laboratory in Hertfordshire, and emeritus group leader at Francis Crick Institute.

 

Aziz Sancar: Nucleotide excision repair
Sancar studied medicine in Istanbul and worked as a doctor for several years, but preferred working as a researcher and began to study biochemistry. In the course of his scientific work, one phenomenon puzzled him: Some bacteria were able to recover from a ‘deadly’ dose of UV radiation if exposed to visible blue light. He set out to find the molecular mechanism behind this effect. While writing his doctoral thesis at the University of Texas in Dallas, he succeeded in cloning the gene for photolyase, an enzyme that can repair UV damage in DNA, and was even  able to breed bacteria that could produce this enzyme. This result became his doctoral thesis, but the scientific community apparently was not impressed at this point. When Sancar couldn’t find a postdoc position, he started working as a lab technician at Yale University School of Medicine in order to continue his research, where he started work that ultimately led to the Nobel Prize 2015.

 

 

Sancar discovered that there wasn’t only the light-dependent photolyase repair mechanisms, but also a ‘dark’ mechanism that can remove several nucleotides damaged by UV radiation completely and replace them. Compared to Lindahl’s base excision repair, rather ‘bulky’ DNA material could be removed by what he called ‘nucleotide excision repair‘. After he published his results in 1983, he was offered a position as associate professor at the University of North Carolina in Chapel Hill, where he still is a professor for biochemistry and biophysics. He is a Turkish-american dual citizen and the second Turkish national to win a Nobel Prize, the first being Orhan Pamuk who was awarded the 2006 Nobel Prize in Literature.

 

Paul Modrich: Mismatch repair
Paul Modrich was a doctoral student at Stanford, had a postdoc position at Harvard and became professor at Duke University in Durham, North Carolina, where he still is today. Among other enzymes, Modrich studied ‘Dam methylase’ extensively, an enzyme that adds methyl groups to DNA. But the signalling function of Dam methylase was still under debate. Together with Harvard geneticist Matthew Meselson, Modrich created viruses with several mismatches in their DNA, and several methyl groups were added as well. Now when bacteria were infected with these viruses, the bacteria automatically corrected the mismatches in each DNA strand that didn’t possess a methyl group.

 

 

The molecular biologists concluded that DNA ‘mismatch repair‘ is a natural process occurring during cell division, and that damaged strands are recognised by their unmethylated state. Modrich studied this repair mechanism in great detail and was able to map all the enzymes involved. His work was published in 1989. Modrich estimated that the repair mechanism he discovered reduced errors during cell replication by about a thousandfold – healthy cells could hardly replicate withouth this important mechanism.

All three Nobel Laureates continued their studies into the repair mechanisms they discovered and found that they all play an important part in human DNA maintenance and health: Thousands of DNA repairs are made by each mechanism inside a human body every day, and malfunctions can lead to serious diseases, mostly cancers, and even death. For instance, congenital damage to the nucleotide excision repair process causes patients to be extremely sensitive to UV radiation, and they develop skin cancer after sun exposure. And defects in DNA mismatch repair increase the risk of developing hereditary colon cancer.

 

 

As the Nobel committee said today: these important, pioneering discoveries “opened up the field” for further research and applications, for instance in cancer research and treatment.

Congratulations to all three Laureates, and we sincerely hope to hear about your groundbreaking discoveries in the upcoming Lindau meetings!

 


Images used in slider graphic are property of Nobel Media, Illustrations by N. Elmehed

Susanne Dambeck

About Susanne Dambeck

Susanne Dambeck is a science writer in English and German, and author of several nonfiction childrens' books. A political scientist by training, she has worked in politics, television and as a biographer. Apart from scientific findings, she is interested in people and in storytelling in different languages.

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