Nobel Prize in Chemistry 2015: Mechanistic Studies of DNA Repair

This note covers the Nobel Prize in Chemistry 2015: who won it, how cells repair damage to their DNA through base excision repair, nucleotide excision repair and mismatch repair, how the discovery unfolded across three independent research careers, why it matters for cancer and ageing, and quick facts for exams.

What was the Nobel Prize in Chemistry 2015 awarded for?

The official citation reads: "for mechanistic studies of DNA repair". The Nobel Prize in Chemistry 2015 went to three scientists who, working separately, worked out in molecular detail how living cells detect and fix damage to their DNA.

In plain words, every cell's DNA is constantly being damaged, by chemical instability inside the cell, by radiation and chemicals from outside, and by small copying mistakes made every time DNA is duplicated.

If none of this damage were corrected, the genetic instructions that keep an organism alive and let it pass traits to offspring would quickly become unreadable.

The three laureates discovered and described the molecular toolkits that cells use to find such damage and repair it, almost like a built-in proofreading and repair service running continuously inside every cell.

The prize's official name is the Nobel Prize in Chemistry, awarded by the Royal Swedish Academy of Sciences.

Who are the laureates?

Tomas Lindahl

Tomas Lindahl was born on 28 January 1938 in Stockholm, Sweden. At the time of the award he was affiliated with the Francis Crick Institute and the Clare Hall Laboratory, both in Hertfordshire, United Kingdom, and he received one third of the prize.

Lindahl showed, from the early 1970s, that DNA is a chemically unstable molecule that decays spontaneously even without any outside attack, and he went on to identify the enzyme system now called base excision repair.

Paul Modrich

Paul Modrich was born on 13 June 1946 in Raton, New Mexico, USA. At the time of the award he was affiliated with the Howard Hughes Medical Institute and Duke University School of Medicine, both in Durham, North Carolina, USA, and he received one third of the prize.

Modrich worked out how cells use methyl-group markers on DNA strands to find and correct the mismatched base pairs that sometimes slip in during DNA copying, a system called mismatch repair.

Aziz Sancar

Aziz Sancar was born on 8 September 1946 in Savur, Turkey. At the time of the award he was affiliated with the University of North Carolina, Chapel Hill, USA, and he received one third of the prize.

Sancar mapped nucleotide excision repair, the mechanism that cells use to cut out and replace DNA segments damaged by ultraviolet light and by cancer-causing chemicals.

What problem were the laureates trying to solve?

By the early 1970s scientists believed DNA, the molecule that stores an organism's genetic information, was extremely stable, because evolution needs only a small, controlled number of mutations per generation. If DNA changed too easily, no complex multicellular life could survive.

Tomas Lindahl began questioning this while working with the related molecule RNA, which degraded rapidly whenever he heated it in his experiments at Princeton University.

Since RNA was already known to be less stable than DNA, he wondered: could even DNA itself be slowly decaying, unnoticed, inside living cells? Back in Sweden at Karolinska Institutet, his experiments confirmed it: DNA underwent a slow but measurable chemical decay, with thousands of potentially harmful changes occurring in a cell's genome every day, a rate that the press release described as something that "ought to have made the development of life on Earth impossible" unless some repair process existed.

Separately, researchers already knew that ultraviolet light damages DNA and that some cells could recover afterwards, and that copying errors occur whenever DNA is duplicated during cell division.

The scientific background to the prize adds scale to this problem: each time a cell divides, the cell must copy more than three billion DNA base pairs, and the human body contains roughly 3.7 × 10¹³ cells. Even a highly efficient copying process will therefore make occasional mistakes, and over a lifetime these mistakes would inevitably pile up without correction.

DNA's instability was described as both a danger and a necessity. Damage can block essential processes such as copying and reading genes, and it can also introduce mutations linked to cancer, nerve-cell diseases and biological ageing; yet without any mutations at all, the gradual change that drives evolution by natural selection would not happen either.

The shared question behind all three laureates' work was the same: what molecular machinery keeps correcting these constant sources of damage, so that genetic information survives essentially unchanged across countless cell divisions and generations?

How does base excision repair work?

Lindahl's chosen path to answering this question started with a specific chemical weakness: the DNA base cytosine can spontaneously lose part of its structure (an amino group) and effectively turn into uracil, a base that does not belong in DNA.

If left uncorrected, this change causes a mutation the next time the DNA is copied, because the altered base pairs wrongly with adenine instead of guanine.

Using bacterial DNA, which like human DNA is built from the four bases adenine, guanine, cytosine and thymine, Lindahl searched for an enzyme that could spot and remove such damaged bases.

In 1974 he identified a bacterial enzyme, a uracil-DNA glycosylase, that strips out these faulty remains of cytosine, the discovery that opened up the entire field of DNA repair research. Two years later he found a second such enzyme that targets a different chemically altered base.

Over the following decades, including time spent at a cancer research institute in London before he became director of the newly founded Clare Hall Laboratory in 1986, he pieced together the full base excision repair pathway, and in 1996 he successfully recreated the equivalent human repair process outside a living cell (in vitro).

The basic steps of base excision repair, as described in the scientific background, are:

1. A specialised enzyme called a DNA glycosylase recognises a damaged base, kinks the DNA so that the abnormal base flips outward, and cuts the bond holding it to the DNA backbone, releasing the faulty base.
2. An enzyme called an AP endonuclease cuts the DNA backbone at the resulting gap, preparing the site for repair.
3. A repair enzyme (a DNA polymerase) fills in the correct nucleotide, using the undamaged strand as a template, while also removing the leftover sugar-phosphate fragment.
4. A final enzyme, DNA ligase, seals the backbone, restoring an intact, correctly paired DNA strand.

This system now explains more than one type of lesion. Scientists have since identified over a hundred different oxidative injuries to DNA bases, and the great majority of them are corrected through this same base excision pathway rather than by a separate mechanism for each kind of damage.

Draw a short stretch of double-stranded DNA with one damaged base (for example a deaminated cytosine) on one strand.

Show an enzyme removing just that single damaged base, leaving a gap, then a second enzyme filling the gap with the correct base and a final enzyme sealing the strand, so the DNA returns to its normal double helix.

How do nucleotide excision repair and mismatch repair work?

Aziz Sancar's path began with a different puzzle: bacteria killed by a severe dose of UV radiation could sometimes recover if afterwards exposed to ordinary blue light, a phenomenon he found almost magical as a biochemistry student.

Working first on the light-dependent repair enzyme photolyase, which he had cloned as a PhD student in 1978, and later moving to Yale University School of Medicine, Sancar turned to a separate, light-independent ("dark") repair system known to depend on three bacterial genes, uvrA, uvrB and uvrC.

By identifying, isolating and studying the enzymes made from these three genes, Sancar showed in a paper published in 1983 that they work together to cut out a UV-damaged stretch of DNA, removing a fragment of about 12 to 13 nucleotides that includes the injury.

In more molecular detail, two copies of the UvrA protein and one copy of UvrB first track along the DNA until UvrA recognises the damaged site, after which UvrB unwinds the DNA locally and a single UvrC protein joins, and UvrB and UvrC together make the two cuts, one on each side of the lesion, before the damaged fragment is pulled away and the gap is filled and sealed.

This mechanism, nucleotide excision repair, uses a broadly similar cut-and-patch strategy in human cells, although more than fifteen proteins are needed to run it there, compared with only three in bacteria.

Paul Modrich's own work grew out of his study of an enzyme called Dam methylase, which adds methyl-group "tags" to DNA, a project he moved into after already studying DNA ligase, DNA polymerase and a restriction enzyme called EcoRI.

Working with Matthew Meselson, Modrich showed that these methyl tags let a bacterium tell its original DNA strand apart from a freshly copied strand, because the new strand briefly lacks the tag.

This let the cell's repair machinery know which strand contained the error and needed correcting, a system called mismatch repair. By 1989 Modrich had rebuilt the whole process using purified components outside a cell, and later, in 2004, he managed the same feat with purified human proteins.

In human cells, methylation does not mark the new strand the way it does in bacteria, so scientists still are not certain exactly how the correct strand is identified there, even though the overall repair process is closely related.

Draw a DNA double helix just after copying, with one strand labelled "original, methylated" and the other labelled "new, unmethylated", and a mismatched base pair between them.

Show the repair proteins recognising the unmethylated strand, cutting out the section around the mismatch, and replacing it using the original strand as the template.

How did the discovery unfold?

Why does it matter?

These repair pathways explain how cells keep their genetic information usable despite constant chemical and environmental assault, and they clarify the causes of several inherited diseases.

The scale of the ongoing repair work is large: mismatch repair alone corrects roughly a thousand mismatched bases at every single round of DNA copying, and it lowers the overall error rate so much that the mutation rate in human reproductive cells is estimated at only about one error per hundred million base pairs copied, per generation.

The press release notes that congenital defects in nucleotide excision repair cause the disease xeroderma pigmentosum, in which people develop skin cancer after exposure to sunlight, while defects in mismatch repair are known to cause a hereditary form of colon cancer.

The work also matters for cancer treatment. In many cancers, one or more DNA repair systems have been partly or fully switched off, making the cancer cell's DNA unstable; this is one reason cancer cells mutate often and can become resistant to chemotherapy.

At the same time, such cells become more dependent on whichever repair systems they still have working.

Researchers have used this weakness to design drugs, such as olaparib, that block a cancer cell's remaining repair system so that its DNA damage becomes too severe for the cell to survive, while healthy cells, which still have all their repair systems intact, are less affected.

The same instability that threatens health also has a positive side: deliberately damaging DNA with radiation or chemicals, which halts cell division and triggers cell death, is itself one of the standard tools used to treat cancer.

Open questions remain too: in human mismatch repair, scientists still do not know for certain how the cell tells the original DNA strand apart from the newly copied one, since the methylation signal that bacteria use does not work the same way in human cells.

How does this connect to what you study?

This prize connects directly to the biology topics of DNA structure and cell division taught in school science. A student learning that DNA carries genetic information in a sequence of bases is really learning about the very molecule these three laureates studied at the chemical level.

DNA replication, the process of copying DNA before a cell divides, is never perfectly accurate, which is exactly the problem mismatch repair solves. Understanding that more than three billion base pairs are copied at every division, and that occasional mistakes are unavoidable, helps explain why cells need a dedicated correction system rather than relying on a perfect copying machine.

Likewise, learning that UV light damages DNA, and that this damage is linked to skin cancer, builds directly on Sancar's work on nucleotide excision repair, which explains at the molecular level why sun exposure can be dangerous and why organisms have evolved defences against it.

The idea that DNA itself slowly decays through ordinary chemical reactions such as deamination, which Lindahl demonstrated, also connects to basic chemistry lessons on how molecules react with water and oxygen, showing students that even the molecule of heredity obeys the same chemical rules as everything else.

Finally, the link between faulty repair genes and diseases such as xeroderma pigmentosum and hereditary colon cancer connects this prize to genetics topics on inherited disorders, since both conditions arise when a repair gene itself is mutated and passed down through a family.

What happened before these three laureates began their work?

DNA repair research did not start in a vacuum. In the 1920s the geneticist Hermann Muller, who later won the Nobel Prize in Physiology or Medicine, had shown that X-rays could kill cells and cause mutations, but no one yet knew of any cellular process that fixed such damage.

A first clue came in the late 1940s, when Albert Kelner found that shining ordinary visible light onto UV-damaged bacteria dramatically helped them recover growth, a phenomenon called photoreactivation.

Researchers later showed this effect depended on an enzyme, which became known as photolyase, that could repair UV damage using energy absorbed from light; this was the earliest DNA repair enzyme activity ever demonstrated.

Separately, other scientists discovered that UV light creates a specific kind of DNA lesion called a thymine dimer, and that bacteria could also remove such dimers through a light-independent process, which came to be called excision repair because the damaged piece of DNA is literally excised, or cut out.

This earlier work identified three bacterial genes involved in that process, named uvrA, uvrB and uvrC, but by the mid-1970s nobody had yet purified the proteins these genes produced or worked out exactly how they acted on damaged DNA.

It is this gap, the step from knowing that a repair system exists to understanding exactly how its proteins work together at a molecular level, that Lindahl, Sancar and Modrich each closed for their own repair pathway.

Their contribution was therefore not the first hint that cells repair DNA, but the first complete, detailed molecular picture of how several of these repair systems actually function, built piece by piece from genetics, biochemistry and reconstituted test-tube experiments.

Quick facts for exams

The Nobel Prize in Chemistry 2015 was announced on 7 October 2015 by the Royal Swedish Academy of Sciences and awarded jointly to Tomas Lindahl, Paul Modrich and Aziz Sancar, each receiving one third of the prize, "for mechanistic studies of DNA repair".

Lindahl, working in the United Kingdom, discovered base excision repair; Sancar, working in the United States, mapped nucleotide excision repair, which fixes UV damage; and Modrich, also in the United States, explained mismatch repair, which corrects errors made while DNA is copied.

Their combined findings show how cells continuously detect and fix DNA damage, with direct relevance to understanding cancer and ageing.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• DNA repair — the set of cellular processes that detect and correct damage or errors in the DNA molecule.
• Base excision repair — the pathway that removes a single damaged base from DNA and replaces it, discovered by Tomas Lindahl.
• Nucleotide excision repair — the pathway that cuts out and replaces a short stretch of DNA containing bulky damage, such as that caused by UV light, mapped by Aziz Sancar.
• Mismatch repair — the pathway that corrects wrongly paired bases introduced during DNA copying, explained by Paul Modrich.
• Glycosylase — an enzyme that recognises and removes a specific damaged base from DNA during base excision repair.
• Photolyase — a light-activated enzyme that repairs UV-induced DNA damage using energy from visible light.
• Deamination — a chemical reaction in which a base such as cytosine loses an amino group, creating damage that can cause mutations.
• Methylation — the attachment of a methyl group to DNA, used by bacteria as a marker to distinguish an original strand from a newly copied one.
• Xeroderma pigmentosum — a hereditary disease caused by defects in nucleotide excision repair, causing extreme sensitivity to UV radiation and skin cancer.
• Mutation — a permanent change in the sequence of DNA, which can occur if damage is not repaired before DNA is copied.
• In vitro — an experiment carried out outside a living cell, for example using purified enzymes in a test tube.
• Olaparib — a cancer drug mentioned as an example of a medicine that blocks a DNA repair system in cancer cells.

Common errors and misconceptions

• Misconception: DNA is a chemically stable molecule that does not change on its own. Correct: Lindahl showed DNA decays spontaneously even without outside damage, through reactions such as deamination.
• Misconception: There is only one DNA repair mechanism. Correct: Cells have several distinct repair pathways, including base excision repair, nucleotide excision repair and mismatch repair, each handling a different kind of damage.
• Misconception: Nucleotide excision repair and base excision repair are the same process. Correct: Base excision repair removes a single damaged base; nucleotide excision repair cuts out and replaces a whole short stretch of DNA around bulky damage.
• Misconception: Mismatch repair prevents all copying errors. Correct: Mismatch repair greatly reduces, but does not eliminate, errors from DNA replication.
• Misconception: The three laureates worked together as a team. Correct: Lindahl, Modrich and Sancar carried out their research independently of each other, on different repair systems.
• Misconception: The prize was for discovering the structure of DNA. Correct: The 2015 Chemistry prize was for studies of how damaged DNA is repaired, not for DNA's structure, which was a separate, earlier discovery.

Exam-style questions with model answers

Q1. For what citation was the Nobel Prize in Chemistry 2015 awarded? [1 mark]

1. It was awarded "for mechanistic studies of DNA repair".

Q2. Name the three laureates of the Nobel Prize in Chemistry 2015 and state their country of birth. [2 marks]

1. Tomas Lindahl was born in Sweden, Paul Modrich was born in the USA, and Aziz Sancar was born in Turkey.

Q3. Explain why DNA needs repair mechanisms even without outside damage. [3 marks]

1. Tomas Lindahl showed that DNA decays spontaneously through chemical reactions such as deamination, in which cytosine loses part of its structure and can pair incorrectly with adenine.
2. He estimated that thousands of potentially harmful changes occur in a cell's genome every day from such spontaneous processes alone.
3. Without repair, this rate of damage would make stable genetic information, and therefore life, impossible, so cells must have continuous repair systems working even in the absence of radiation or chemicals.

Q4. Describe how nucleotide excision repair corrects UV damage to DNA. [4 marks]

1. Aziz Sancar identified the bacterial enzymes made from the uvrA, uvrB and uvrC genes, which work together to find UV-damaged DNA.
2. These enzymes make two cuts in the damaged strand, one on each side of the injury.
3. A fragment of about 12 to 13 nucleotides, including the damaged part, is removed from the strand.
4. The gap is then filled in using the undamaged strand as a template, and the backbone is sealed, restoring normal DNA.

Q5. Discuss how the discoveries of the 2015 Chemistry laureates are relevant to cancer. [5 marks]

1. Defects in these repair systems directly cause disease: faulty nucleotide excision repair causes xeroderma pigmentosum, leaving people highly sensitive to UV radiation and prone to skin cancer, while faulty mismatch repair is linked to a hereditary form of colon cancer.
2. In many cancers, one or more DNA repair systems are partly or fully switched off, which makes the cancer cell's DNA unstable.
3. This instability is one reason cancer cells mutate frequently and can become resistant to chemotherapy drugs.
4. However, cancer cells with a weakened repair system become more dependent on whichever repair pathways they still have working to survive.
5. Researchers exploit this weakness with drugs such as olaparib, which block a remaining repair system in the cancer cell, causing DNA damage to build up until the cell dies, while healthy cells with intact repair systems are less affected.

Q6. What is mismatch repair and how does a cell know which DNA strand to correct? [4 marks]

1. Mismatch repair is the pathway that corrects wrongly paired bases introduced while DNA is being copied during cell division.
2. Paul Modrich showed that methyl-group tags on DNA act as signals, marking the original strand.
3. Because the newly copied strand briefly lacks this methyl tag, the cell's repair machinery can identify it as the strand that may contain the error.
4. The repair proteins then cut out and replace the faulty section of the unmethylated, newly copied strand, using the original strand as the template.

Q7. Who mapped base excision repair, and what was the key early discovery behind it? [3 marks]

1. Tomas Lindahl mapped the base excision repair pathway.
2. His key early discovery, published in 1974, was a bacterial enzyme that removes damaged, deaminated cytosine bases from DNA.
3. This was the first identified repair enzyme in this pathway and opened up the whole field of DNA repair research.

Q8. State the prize amount and the share each laureate received for the Nobel Prize in Chemistry 2015. [2 marks]

1. The prize amount was 8,000,000 Swedish kronor, shared equally among the three laureates, with each receiving one third.

Key takeaways

• The Nobel Prize in Chemistry 2015 honoured Tomas Lindahl, Paul Modrich and Aziz Sancar for mechanistic studies of DNA repair.
• Lindahl discovered that DNA decays spontaneously and mapped base excision repair, which removes single damaged bases.
• Sancar mapped nucleotide excision repair, which cuts out and replaces DNA stretches damaged by UV light and carcinogens.
• Modrich explained mismatch repair, which corrects copying errors using methyl-group markers to identify the new DNA strand.
• Faulty nucleotide excision repair causes xeroderma pigmentosum; faulty mismatch repair is linked to hereditary colon cancer.
• Many cancers switch off one or more repair systems, and drugs such as olaparib exploit the cancer cell's remaining weakness.
• Each laureate worked independently and received one third of the 8,000,000 Swedish kronor prize.

Test yourself

What was the official citation for the Nobel Prize in Chemistry 2015?

The citation was "for mechanistic studies of DNA repair", awarded jointly to Tomas Lindahl, Paul Modrich and Aziz Sancar.

Where was Tomas Lindahl affiliated at the time of the award?

Tomas Lindahl was affiliated with the Francis Crick Institute and Clare Hall Laboratory, both in Hertfordshire, United Kingdom.

What did Paul Modrich's mismatch repair system correct?

Mismatch repair corrects wrongly paired bases that are sometimes introduced into DNA while it is being copied during cell division.

What type of damage does nucleotide excision repair fix?

Nucleotide excision repair fixes bulky DNA damage, such as that caused by ultraviolet light or cancer-causing chemicals.

What disease results from defects in nucleotide excision repair?

Defects in nucleotide excision repair cause xeroderma pigmentosum, making people highly sensitive to UV radiation and prone to skin cancer.

How does a cell distinguish the newly copied DNA strand during mismatch repair?

The newly copied strand briefly lacks a methyl-group tag that marks the original strand, letting repair proteins identify it.

Name one drug mentioned that exploits weakened DNA repair in cancer cells.

Olaparib is a drug that inhibits a remaining DNA repair system in cancer cells to slow or stop their growth.

How much prize money was awarded and how was it shared?

The prize was 8,000,000 Swedish kronor, shared equally among the three laureates, each receiving one third.