DNA repair: how cells fix their own genes

What DNA is

DNA (deoxyribonucleic acid) carries the instructions for building and running a living thing Grade 10: DNA. It is a long, thin molecule shaped like a twisted ladder, the double helix. Each side of the ladder is a strand. The rungs are made of four chemical bases, written with four letters: A, T, G and C. Each rung is a pair, and the pairs always match: A with T, and G with C.

The order of the letters is the message, like the order of letters in a word. Because the pairs match, each strand carries the same message, written in matching letters. When a cell divides, the two strands come apart and each is used as a pattern to build a new partner.

A change in the letters is called a mutation Grade 9: Mutation. One wrong letter can spoil the instructions for a protein (One wrong letter), and mutations in the wrong genes can turn a cell into a cancer cell.

Everyone thought DNA was tough

In the 1960s, scientists believed DNA must be extremely stable. It had to be: if the instructions of life kept changing, how could a cat’s kittens be cats?

The Swedish scientist Tomas Lindahl began to doubt this. As a young researcher at Princeton University in the USA, he worked on RNA, a close chemical cousin of DNA Grade 10: RNA. His experiments kept failing, because the RNA broke down when he heated it. RNA was known to be more fragile than DNA. But if RNA fell apart so easily, could DNA really last a whole lifetime?

1. The damage is tiny. A damaged spot is one or a few atoms out of place in a molecule billions of atoms long. You cannot see it, even with a microscope.
2. The repair workers are tiny too. The cell’s repairs are done by enzymes: proteins that make one chemical reaction happen. A cell has thousands of different proteins, and the scientists had to find the few that do each repair, purify them, and work out what each does, one by one.
3. Starting with bacteria. Most of the work began with E. coli, a common bacterium of the human gut, which grows fast and is easy to change. Bacteria have the same four letters in their DNA, so what is learned in them often holds for us, but every step then had to be checked in human cells.

Lindahl: DNA falls apart, so it must be repaired

1. Early 1970s, the decay. Back in Stockholm, at the Karolinska Institute, Lindahl did simple experiments and found that DNA does slowly decay, even in conditions like those inside a cell. He worked out that each cell’s DNA should suffer thousands of damaging changes every day. With that much damage, life could not exist. So, he reasoned, cells must have ways of repairing it.
2. A weak letter. One weakness is the letter C (cytosine). It easily loses a small group of atoms (an amino group, NH₂). What is left is a different base, U (uracil), which pairs with A instead of G. When the DNA is next copied, the wrong letter is built in.
3. 1974, the first repair enzyme. In E. coli, Lindahl found an enzyme that recognizes the damaged C and cuts that one base out. Other enzymes then remove the empty spot and put back a correct C, using the other strand as the pattern. This is base excision repair (excision means cutting out).
4. 1996, in a test tube. After years of finding the other enzymes, by then working in Britain, Lindahl rebuilt the whole human version of base excision repair in a test tube.

Sancar: repairing damage from sunlight

Aziz Sancar grew up on a farm in south-eastern Turkey. He studied medicine in Istanbul and then worked as a doctor in villages near his home town, often the first doctor his patients had ever seen. But he wanted to understand how medicines and cells work, so he went to the USA to study biochemistry, the chemistry of living things.

1. A light that heals. Bacteria killed by ultraviolet (UV) light Grade 9: Ultraviolet rays can come back to life if they are then lit with ordinary blue light. In Texas, in the mid-1970s, Sancar copied the gene for the enzyme behind this, photolyase, and made bacteria produce it in large amounts. Our own cells don’t have this light-powered enzyme.
2. Rejected. When he finished his PhD in 1977, he applied to three leading laboratories and was turned down by all three. He took a place in a laboratory at Yale University instead, where others were studying a second way bacteria repair UV damage, which works in the dark.
3. The cutting enzymes. Three genes, called uvrA, uvrB and uvrC, were known to be needed. Sancar isolated the three enzymes they make. UV light often makes two T letters that sit side by side stick together, putting a kink in the DNA. Sancar showed that the enzymes find the kink and cut the strand on both sides of it, removing a short piece 12 or 13 letters long. The gap is then filled by copying the other strand. He published this in 1983. It is called nucleotide excision repair.
4. In humans too. At the University of North Carolina, he and others worked out the human version. It uses more enzymes, but the chemistry is the same.

Modrich: correcting copying mistakes

Paul Modrich grew up in a small town in New Mexico, where his father taught biology. In 1963, the year after Watson and Crick won the Nobel Prize for the structure of DNA, his father told him: “You should learn about this DNA stuff.”

1. Tags on DNA. In the late 1970s, at Duke University, Modrich studied an enzyme that sticks small chemical tags, methyl groups (CH₃), onto bacterial DNA.
2. A puzzle from Harvard. Matthew Meselson, an American scientist, had noticed that bacteria correct DNA in which a letter is mismatched (say, G opposite T instead of C). In 1976 he suggested this might fix mistakes made while copying DNA. But how would the cell know which of the two letters was wrong? Perhaps, he suggested, by the tags: the new strand has not been tagged yet.
3. The test. Modrich and Meselson made viruses with mismatches in their DNA and tags on only one strand. The bacteria they infected always corrected the untagged strand. So the tags tell the cell which strand is the old, trusted one.
4. 1989, in a test tube. Over ten years, Modrich found each enzyme of this mismatch repair and rebuilt the whole process in a test tube.

When human DNA is copied, mismatch repair fixes all but about one in a thousand of the copying mistakes that slip past.

All three repair kits use the same trick. Because the two strands carry matching letters, the cell keeps a backup copy of every message. Damage is almost always on one strand only. So the cell can cut out the damaged piece and rebuild it, letter by letter, from the healthy strand opposite.

These are not the only repair kits. Cells have several others, for example to rejoin DNA that has broken right across both strands. Together, they fix thousands of pieces of damage in every cell every day, and about a thousand copying mismatches every time a human cell divides.

• Sunburn. UV light from the Sun damages the DNA in your skin cells, and sunburn is partly the body’s reaction to that damage. Nucleotide excision repair cuts out most of it. UV gets stronger the higher you go, by roughly a tenth for every 1,000 m, so in Nepal’s hills and mountains, sun cream, a hat and sunglasses matter even when the air is cool.
• When repair fails. Children born with a faulty nucleotide excision repair gene have a rare disease, xeroderma pigmentosum: they must keep out of sunlight, because their skin gets cancer very easily. People who inherit a faulty mismatch repair gene are more likely to get some cancers, such as cancer of the colon (part of the large intestine).
• Cancer medicines. In many cancers one repair kit is broken. That makes the cancer cells depend heavily on the kits they have left. A medicine called olaparib blocks one of those, so the cancer cells’ DNA becomes too damaged and they die. It is used for some cancers of the breast, ovary and prostate.

• Medicines from broken repair. Since 2017, some cancer medicines that help the body’s own defenses attack a tumor have been given according to whether the tumor’s mismatch repair is broken, whatever part of the body it started in: a tumor full of mutations is easier for the defenses to recognize.
• Body clocks. Sancar went back to photolyase and helped show that its relatives in our own cells, which repair nothing, help keep the body’s daily clock.
• Open questions. In human cells, how does mismatch repair tell the new strand from the old? Our DNA doesn’t use tags in the way bacteria do, and the full answer is still being worked out. Scientists are also studying how much worn-out repair adds to aging.

• Grade 9: mutation and variation; ultraviolet rays.
• Grade 10: DNA, RNA, chromosomes and cell division, when DNA is copied.
• Grade 8: bacteria.
• Going further: one wrong letter, copying errors in every child and mutations from outside.

• The Nobel Prize’s own explanation: DNA repair – providing chemical stability for life (nobelprize.org).
• The Nobel lectures: Lindahl, Modrich and Sancar.

The prize was given “for mechanistic studies of DNA repair.”

This prize at nobelprize.org(opens in a new tab)