Trio gets chemistry Nobel for figuring out DNA repair

On October 7, three scientists won the 2015 Nobel Prize in chemistry for their studies of DNA repair. They identified the molecular repair kits. Cells use these to fix damaged DNA.

Tomas Lindahl is a researcher at the Francis Crick Institute in Potters Bar, England. Paul Modrich is a Howard Hughes Medical Institute investigator at Duke University School of Medicine in Durham, N.C. Aziz Sancar works at the University of North Carolina School of Medicine in Chapel Hill. The trio 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 Claes Gustafsson. The molecular biologist is a member of the Nobel Committee for Chemistry. He spoke at a news conference announcing the prize.

Long, spiral-shaped molecules of DNA exist inside the cells of every living organism — from people to plants to bacteria. DNA contains the instructions for building proteins needed for each organism’s survival. The instructions are spelled out in a winding string of chemical building blocks. Those building blocks, called nucleotides, contain a molecular backbone and either adenine, thymine, cytosine or guanine. They are symbolized by four DNA “letters” — A, T, C and G. Those letters are used over and over again to spell out thousands of genetic “words.”

This string of DNA is fragile, though. It constantly collects bumps and bruises. Sunlight can fuse neighboring letters together. 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. If that damage was not repaired, it would build up and trigger diseases. Every form of cancer starts with some kind of DNA damage or error, Gustafsson pointed out. Scientists now have a good idea of how repair kits inside cells 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 Martyn Poliakoff. He is a chemist at the University of Nottingham in England. “This is very important fundamental science.”

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

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

How they solved the puzzle

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, [Lindahl] 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.” (U stands for uracil. This chemical is not normally found in DNA.) 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. It was a bacterial enzyme that snips out U letters. This was the first step in the repair process. Different enzymes finish the job and patch up the hole.

(Story continues below image)

From the early 1980s to 1990, Modrich’s work also focused on how a cell corrects genetic spelling typos. In DNA, certain letters always pair together, forming what are known as base pairs. A goes with T. C pairs with G. Mismatches can prevent DNA from functioning properly.

Modrich identified molecules that monitor a stretch of genetic material. Those molecules find mismatches. Then they chop out the offending region. Afterward, they replace it with the correct pattern of DNA. This process is known as DNA mismatch repair. Modrich observed it in bacterial cells and later in animal cells, including human ones.

In 1983, Sancar described the first step of a third DNA repair mechanism. That one is called nucleotide excision repair. It fixes damage from ultraviolet light. That type of light is found in sunlight and is what makes the sun’s rays dangerous. He identified three bacterial proteins that slice out short sections of DNA with inappropriately fused letters. He later outlined the next steps of repair. That is when enzymes fill the blank spots with fresh letters and seal up the gap. Similar versions of the repair kit are at work in all organisms. But more proteins are involved in humans.

All of this sounds like biology. But the prize is for chemistry. The reason? The laureates’ work is “chemistry in a biological context,” explains Diane Grob Schmidt. She is president of the American Chemical Society and a chemist at the University of Cincinnati in Ohio. “I’m delighted with the selections.” The prize recognizes the critical role that chemistry plays in drafting the blueprints of life, she says.

Power Words

(for more about Power Words, click here)

bacterium (plural bacteria) A single-celled organism. These dwell nearly everywhere on Earth, from the bottom of the sea to inside animals.

base excision repair  A system for repairing damaged DNA. Cytosine (C) in DNA can degrade into uracil (U). This mechanism replaces the Us with Cs and also provides fixes for other types of damage.

base pairs  (in genetics) Sets of nucleotides that match up with each other on DNA or RNA. For DNA, adenine (A) matches up with thymine (T), and cytosine (C) matches up with guanine (G).

biochemistry  A field that marries biology and chemistry to investigate the reactions that underpin how cells and organs function. People who work in this field are known as biochemists.

biology  The study of living things. The scientists who study them are known as biologists.

cancer Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.

cell   The smallest structural and functional unit of an organism. Typically too small to see with the naked eye, it consists of watery fluid surrounded by a membrane or wall. Animals are made of anywhere from thousands to trillions of cells, depending on their size.

chemical  A substance formed from two or more atoms that unite (become bonded together) in a fixed proportion and structure. For example, water is a chemical made of two hydrogen atoms bonded to one oxygen atom. Its chemical symbol is H₂O.

chemistry  The field of science that deals with the composition, structure and properties of substances and how they interact with one another. Chemists use this knowledge to study unfamiliar substances, to reproduce large quantities of useful substances or to design and create new and useful substances. (about compounds) The term is used to refer to the recipe of a compound, the way it’s produced or some of its properties.

DNA (short for deoxyribonucleic acid) A long, double-stranded and spiral-shaped molecule inside most living cells that carries genetic instructions. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.

DNA mismatch repair  A system by which a cell can repair errors in DNA made during replication.

enzymes  Molecules made by living things to speed up chemical reactions.

gene  (adj. genetic) A segment of DNA that codes, or holds instructions, for producing a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.

genetic Having to do with chromosomes, DNA and the genes contained within DNA. The field of science dealing with these biological instructions is known as genetics. People who work in this field are geneticists.

molecular biology  The branch of biology that deals with the structure and function of molecules essential to life. Scientists who work in this field are called molecular biologists.

molecule An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O₂), but water is made of two hydrogen atoms and one oxygen atom (H₂O).

nucleotide excision repair  The mechanism by which a cell fixes DNA damage caused by ultraviolet light.

nucleotides The four chemicals that link up the two strands that make up DNA. They are: A (adenine), T (thymine), C (cytosine) and G (guanine). A links with T, and C links with G, to form DNA.

organism Any living thing, from elephants and plants to bacteria and other types of single-celled life.

proteins  Compounds made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. The hemoglobin in blood and the antibodies that attempt to fight infections are among the better-known, stand-alone proteins.Medicines frequently work by latching onto proteins.

RNA  A molecule that helps “read” the genetic information contained in DNA. A cell’s molecular machinery reads DNA to create RNA, and then reads RNA to create proteins.

ultraviolet A portion of the light spectrum that is close to violet but invisible to the human eye.