Chemistry Nobel granted for deciphering DNA repair

Identifying the molecular repair kits that cells use to fix damaged DNA has won three scientists the 2015 Nobel Prize in chemistry. Tomas Lindahl of the Francis Crick Institute in England, Paul Modrich, a Howard Hughes Medical Institute investigator at Duke University School of Medicine, and Aziz Sancar of the University of North Carolina School of Medicine uncovered three tools for correcting errors in the genetic blueprints of living cells.

Together, the scientists hammered out molecular details of the gadgets “that help to guard the integrity of our genes,” said molecular biologist Claes Gustafsson, a member of the Nobel Committee for Chemistry, at a news conference announcing the prize.

Without a way to repair it, DNA damage would build up and trigger several diseases, including cancer. Scientists now have a good idea of how cells’ repair kits work and the roles they play in other processes such as aging. Lindahl, Modrich and Sancar’s early discoveries in the 1970s and 1980s opened up the field, Gustafsson said.

“It’s a well-deserved prize,” says chemist Martyn Poliakoff of the University of Nottingham in England. “This is very important fundamental science.”

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Sun damage

When exposed to ultraviolet light, neighboring DNA letters can fuse together, making it hard for the cell’s machinery to read them. One type of DNA repair, called nucleotide excision repair, targets this type of damage, snipping out the fused letters and replacing them with correct DNA.

Understanding the nitty-gritty details of cells’ repair machinery is also important for designing effective cancer drugs, says biochemist and structural biologist Laurence Pearl of the University of Sussex in England. “The implications are huge,” he says.

Inside the cells of every living organism — from people to plants to bacteria — lie genetic instructions for the proteins needed for survival. These instructions are spelled out in a winding string of chemical building blocks, symbolized by four DNA “letters” and used over and over again to spell out thousands of genetic words.

This string of DNA is fragile, though, and constantly collects bumps and bruises. Sunlight can fuse neighboring letters together and chemicals in cigarette smoke can glom onto letters, making them hard for the cell’s machinery to read. Even the day-to-day actions of the cell itself can muck up the order of DNA letters.

Tiny mistakes can be disastrous. Every form of cancer starts with some kind of DNA damage or error, Gustafsson pointed out.

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It’s impossible to escape DNA damage, Lindahl said at the news conference. “We live in a world where we get exposed to DNA-damaging agents all the time.” Fortunately, he added, “all living cells have repair systems.”

Lindahl began to puzzle out one of these repair systems, called base excision repair, in the early 1970s. He noticed that RNA, a molecular relative of DNA, was prone to breaking down. “Being a very well-trained chemist, he realized that this chemistry must also be happening in DNA,” Pearl says.

Lindahl was right. Over time, the chemical letter “C” in DNA tends to morph into the letter “U.” In fact, he calculated, this letter conversion happens about 200 times a day in every cell. Without some kind of spell-checker, he reasoned, cells would lose all of their C’s over time.

In 1974, he discovered such a molecular editor: a bacterial enzyme that snips out U letters, the first step in the repair process. Different enzymes finish the job and patch up the hole.

From the early 1980s to 1990, Modrich’s work also focused on how a cell corrects genetic spelling typos. The molecular letters of DNA link together in pairs to build the iconic double helix, A with T or C with G. Mismatches can prevent DNA from functioning properly.

Modrich identified molecules that monitor a stretch of genetic material, find mismatching mistakes, chop out the offending region and replace it with the correct pattern of DNA. Modrich observed this process, known as DNA mismatch repair, in bacterial cells and later in animal cells, including human ones.

In 1983, Sancar described the first step of a third DNA repair mechanism, called nucleotide excision repair, that fixes damage from ultraviolet light. He identified three bacterial proteins that slice out short sections of DNA with inappropriately fused letters. He later outlined the next steps of repair: enzymes fill the blank spots with fresh letters and then seal up the gap. Similar versions of the repair kit are at work in all organisms, although more proteins are involved in humans.

The laureates’ work is “chemistry in a biological context,” says Diane Grob Schmidt, president of the American Chemical Society and a chemist at the University of Cincinnati. “I’m delighted with the selections.” The prize recognizes the critical role that chemistry plays in drafting the blueprints of life, she says.