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Nobel Prizes

DNA's repair tricks win chemistry's top prize

Experiments showed how enzymes keep mutations from wrecking the molecule of life.
Science
16 Oct 2015
Vol 350, Issue 6258
p. 266
Considering how much depends on the messages it bears, DNA is an alarmingly fragile molecule. It's vulnerable to UV light and mutagenic chemicals, as well as spontaneous decay. Life has survived through the ages because enzymes inside every cell ensure that DNA remains in proper working order. This year's Nobel Prize in chemistry, announced 7 October, recognizes three scientists who discovered key mechanisms for fixing the damage. “These are classic studies and a great prize for DNA repair,” says Jacqueline Barton, a chemist at California Institute of Technology in Pasadena.
The discoveries were made in the 1970s and 1980s by Paul Modrich of Duke University School of Medicine in Durham, North Carolina; Aziz Sancar of the University of North Carolina, Chapel Hill—the first Turkish scientist to receive a Nobel—and Tomas Lindahl of the Francis Crick Institute at Clare Hall Laboratory in Hertfordshire, U.K. “I feel very lucky and proud to be selected,” Lindahl said by phone during the press conference in Stockholm at which the prize was announced.
Biologists have long known that DNA wasn't rock solid. Blasts of xrays, for example, could cause mutations in cells. Yet most researchers believed that the molecule was inherently stable. After all, cancer and other genetic malfunctions are the exception, not the rule.
Repair crew
ILLUSTRATION: ADAPTED BY A. CUADRA/SCIENCE FROM © JOHAN JARNESTAD/THE ROYAL SWEDISH ACADEMY OF SCIENCES
As a postdoc in the late 1960s, however, Lindahl began to have doubts. Samples of RNA in his experiments rapidly degraded when heated. Further experiments showed that even under normal conditions, DNA quickly suffered enough damage to make life impossible. A light bulb went on. “Lindahl had the critical insight,” says biochemist Bruce Alberts of the University of California, San Francisco.
Lindahl began to search for enzymes that might repair this unseen damage. Among other things, he studied a malfunction in which a part of the nucleotide cytosine—one of the four bases that make up DNA—degrades at everyday temperatures. When the DNA molecule replicates, this damaged base matches up with the wrong kind of nucleotide, thus introducing errors into the genetic code. Lindahl discovered a process, now called base excision repair, in which enzymes continually spot and replace such interloper bases. He and colleagues described the mechanism in 1974.
At about this time, Sancar, who was working as a doctor in the Turkish countryside, decided he would rather study biochemistry. During his doctoral research at the University of Texas, Dallas, he cloned the gene for photolyase, an enzyme that helps bacteria fix damage from otherwise lethal doses of UV light. Later, while working as a lab technician at Yale University School of Medicine, Sancar un covered another repair mechanism, nucleotide excision repair, which allows cells to fix a different kind of damage from the one Lindahl studied, using different enzymes.
Modrich tackled a third source of error: mistakes that happen during replication, when the two strands of DNA unzip and are copied. A common problem is that a wrong nucleotide is added to the new strand, resulting in an error called a mismatch of base pairs. Enzymes efficiently fix these errors—and Modrich helped figure out how it happens. In the late 1970s, he was studying an enzyme called Dam methylase, which dots DNA with side chains made of carbon and hydrogen atoms, called methyl groups. Modrich's experiments proved that so-called restriction enzymes use these methyl groups as guidemarks for cutting DNA. Subsequent discoveries resulted in a step-by-step description (Science, 14 July 1989, p. 160) of how bacterial enzymes spot, mark, and repair mismatched base pairs in a freshly copied double helix (see diagram).
Many other mechanisms also fix faulty DNA, and many other researchers have made key contributions to their study. That fact has raised the inevitable question of who should have won the Nobel for DNA repair. “Lindahl was a clear choice. That was to be expected,” says Björn Schumacher, who studies DNA repair in aging at the University of Cologne in Germany. But Modrich and Sancar were less familiar to him: “It would be easy to come up with the names of other scientists who are of similar importance,” he says.
Indeed, last month another prestigious prize—the Albert Lasker Basic Medical Research Award, often a predictor of the Nobel—went to two other DNA repair researchers (http://scim.ag/Laskerprizes): Evelyn Witkin of Rutgers University, New Brunswick, in New Jersey (who showed how changes in gene expression help bacteria cope with DNA damaged by UV light), and Stephen Elledge of Brigham and Women's Hospital in Boston (for further discoveries of DNA repair in yeast and humans). But Thomas Carell, who studies nucleic acid chemistry at Ludwig Maximilian University of Munich in Germany, says the Nobel Committee got it right. “This is perfect,” he says. “DNA repair is a hugely important topic, and these three were the first to describe the repair mechanisms.”

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Science
Volume 350 | Issue 6258
16 October 2015

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Published in print: 16 October 2015

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