Nobel Prize for Repairmen

(October 8th, 2015) Two biochemists and a medical scientist win this year’s Nobel Prize for Chemistry. Tomas Lindahl, Paul Modrich and Aziz Sancar taught us how cells repair damaged DNA, brought upon them through oxidation, UV radiation or cell division.

For many, including Thomson Reuters, it was sure as eggs is eggs. The two discoverers of the bacterial defence system-cum-precise genetic engineering tool, Emmanuelle Charpentier and Jennifer Doudna would bag this year’s Chemistry Nobel. But the Nobel committee had different names in mind. Instead of awarding research that is merely three years old, they have acknowledged the lifeworks of three scientists, whose seminal papers were published more than 30 years ago and have since become textbook knowledge.

For their “mechanistic studies of DNA repair”, Tomas Lindahl (born 1938 in Stockholm, Sweden; Emeritus group leader at the Francis Crick Institute and Emeritus director of Cancer Research UK at Clare Hall Laboratory, Hertfordshire, UK), Paul Modrich (born 1946, Duke University School of Medicine, Durham, USA) and Aziz Sancar (born 1946 in Savur, Turkey; University of North Carolina School of Medicine, Chapel Hill, USA) receive the 2015 Nobel Prize in Chemistry.

DNA is not as stable as it was once thought. External factors (UV radiation, genotoxic substances) and internal processes (cell division) can damage the molecule. These lesions, if not corrected, can cause mutations and ultimately disease. But, nature, as clever as it is, has come up with some elegant repair strategies. Base Excision Repair (BER) is one of them.

Tomas Lindahl discovered that, even under physiological conditions, DNA is subject to decay. For instance, spontaneous cytosine deamination leads to the formation of uracil, which is entirely out of place in a DNA molecule and forms base pairs with the “wrong” partner: adenine instead of guanine. Lindahl identified, in 1974, the E. coli uracil-DNA glycosylase (UNG), a repair protein, which releases free uracil from DNA-containing deaminated cytosine residues. The glycosylase recognises and hydrolytically cleaves the base-deoxyribose glycosyl bond of a damaged nucleotide, releasing the abnormal nucleotide.

“I think many people have now realised it’s a very important topic of research. There would be 10, 15 excellent people you could choose from but you can’t give the Nobel Prize to more than three people. So I feel very lucky and privileged to be included in the top class that was awarded,” Lindahl said in a telephone interview after the Prize announcement. One of his research focuses is cancer. “We want to understand repair mechanisms in some detail, so that we can prevent the cancer cells from repairing DNA when we, for example, expose them to radiotherapy. But we do need the repairs to protect us against DNA damage that occurs inevitably,” he added.

Aziz Sancar is the first Turkish-born scientist to win a Nobel Prize. He was still asleep when Stockholm called. “I am of course honoured to get this recognition for all the work I've done over the years, but I'm also proud for my family and for my native country and my adopted country. Especially for Turkey it's quite important,” he told the Chief Scientific Officer of Nobel Media, after having reassured himself he wasn’t dreaming. Sancar was honoured for his work, elucidating the mechanisms of the nucleotide excision repair (NER) pathway. Cells use this pathway to repair UV damage to DNA.

Protein identification was not an easy task in the 1970s but Sancar developed a technique that relied on a UV-repair-deficient bacterial strain. Using this technique, he identified the proteins involved in NER and their functions. In E.coli, three proteins are involved with this repair process. UvrA recognises the damage, UvrB unwinds the DNA around the lesion and makes an incision at the 3’end of the lesion, while UvrC cuts the damaged DNA on the 5’ side. The incised strand is disposed and a new, correct strand synthesised. In humans, this cut-and-patch repair mechanism requires more than 15 proteins.

Last but not least, mismatch repair corrects mistakes that have been introduced to DNA during the imprecise DNA replication process. DNA polymerases check the newly synthesised DNA for errors. Paul Modrich discovered, in the early 1980s, that DNA methylation plays an important role in mismatch repair in E. coli. Nine years later, he could demonstrate the entire process in an in vitro system, revealing the requirements of DNA polymerase III, exonuclease I and DNA ligase. Interestingly, in eukaryotic cells, DNA methylation is of no importance for mismatch repair.

Modrich, who was surprised by the news from Stockholm whilst on holiday in the New Hampshire woods, said “I think the field, for many years, didn't receive the attention that it really deserved. And importantly, it’s now unequivocally established for controlling the production of mutation - both in a positive and negative way”.

Kathleen Gransalke

Photo: Ill. N. Elmehed. © Nobel Media AB 2015

Last Changes: 12.01.2015