This year’s Nobel Prize in Chemistry recognises the discovery of DNA repair, the processes used by all organisms to give DNA the stability required in order to be able to transfer genetic information from one generation to the next. The prize has a particular connection with Gothenburg, as Tomas Lindahl – one of the Nobel Laureates – was a professor at the University of Gothenburg from 1978 to 1982.
It’s not by chance that DNA is used to store genetic information; DNA is considerably more stable than RNA. The most popular theories about how the macromolecules of life came into existence are based on RNA coming first, with DNA appearing later as a long-term storage medium. However, DNA is constantly exposed to impacts leading to its degradation. It is widely known that DNA is damaged by many reactive chemicals, both synthetic and natural, and by electromagnetic radiation with sufficiently high energy (UV, X-, and gamma radiation). The actual replication process also contributes a certain error frequency. But spontaneous DNA damage also occurs without the influence of obvious external factors. This happens more quickly in aqueous solutions, at higher temperatures and in the presence of oxygen, but a certain degree of degradation also takes place when free DNA is in a dry, cold environment and protected against the oxygen in the air.
The origin of the discoveries leading to the 2015 Nobel Prize in Chemistry was the insight that this degradation rate was so high that it would be impossible for DNA to be preserved intact even during an individual’s lifetime unless it was counteracted by something. An active cellular process was necessary in order to explain the observed stability in living organisms: DNA repair. The DNA repair systems are evolutionarily conserved, and stretch back billions of years. They are the same in bacteria, animals and plants. Two challenges they have faced were when life was exposed to UV light on the surface of the planet and when the atmosphere became oxidising as oxygen started to be formed on a large scale through photosynthesis.
Paul Modrich researched mismatch repair – when the bases opposite each other in DNA are not in accordance with the Watson-Crick rules: adenine with thymine, and cytosine with guanine. Such errors usually occur through DNA replication mistakes. To correct this, and to replace the incorrect base with the correct one, it is necessary to discriminate between the newly formed DNA strand (with the incorrect base) and the old strand. Modrich discovered that what is recognised are the chemical differences between the strands immediately after replication – single-strand breaks and pieces of RNA in the new strand. DNA replication is by far the most precise process in biology (with an error frequency of < 10-9), with mismatch repair contributing at least two orders of magnitude.
Aziz Sancar characterised nucleotide excision repair, a mechanism which is the first line of defence to eliminate damage caused by UV light from the sun. Here, a section of DNA is removed from the damaged strand, and the cell then synthesises new DNA to fill the gap. Nucleotide excision repair is also used for many other types of damage. Hereditary defects in nucleotide excision repair in humans result in hypersensitivity to sunlight and an increased cancer risk, particularly of the skin.
Tomas Lindahl discovered base excision repair. This mechanism uses the enzymes DNA glycosylases, which remove only the actual damaged base from DNA. The first example was how the cell repairs a very common defect that occurs spontaneously: changing cytosine into uracil. Uracil is present in RNA, but should not be present in DNA. A DNA glycosylase that specialises in uracil eliminates it from DNA – an operation which it needs to carry out approximately 100 times a day in each and every cell (or 1015 times per day throughout the entire body). DNA damage from oxygen occurs particularly often in the mitochondria, where oxygen is used in the cellular respiration that gives us our energy. The mitochondria therefore contain DNA glycosylases which have the task of repairing this damage.
In simple terms, Modrich’s discovery of mismatch repair explains how cells deal with the errors that arise in connection with replication; Sancar’s characterisation of nucleotide excision repair clarifies how we address the DNA damage caused by UV light from the sun, while base excision repair – Lindahl’s discovery – is our most important mechanism for dealing with the threat to DNA from oxygen in the air. There are more repair mechanisms than these three to fix DNA damage. The potentially most dangerous of all types of damage is double-strand breaks, where both DNA strands are damaged within a short distance. This occurs primarily as a result of ionising radiation (X- and gamma radiation). The base pairing in the DNA then fails to hold the molecule together and it can separate into two parts – a chromosome break has occurred. Preventing this is a top priority, and the cell has several mechanisms for repairing double-strand breaks in DNA.
Tomas Lindahl was a true pioneer in the field of DNA repair. In the early 1980s I spent a period carrying out experimental work in his lab while completing my first-cycle studies. My timetable only allowed me to visit the lab during evenings and weekends. Yet I was rarely alone there, since there were plenty of visiting researchers from different countries, all of whom busy working. It was only later that I realised that not all research environments are quite so lively. A decade later, Lindahl – as an authority on DNA stability – published a summary of the feasibility of recovering DNA from archaeological finds from different epochs. This provided essential support for another Swede in exile, Svante Pääbo, in his search for Neanderthal DNA
As well as enabling us to survive, DNA repair is important in connection with cancer and its treatment. As mentioned, DNA repair defects confer an elevated cancer risk. But when treating cancer with radiation or cytotoxic drugs (DNA-damaging substances that produce mutations), the outcome depends on the tumour cells’ ability to repair DNA. This is often affected by mutations. We can try to improve the results by inhibiting the tumour cells’ DNA repair enzymes, which gives a greater chance of eradicating the tumour. Although this Nobel Prize recognises pure fundamental research, it has also found applications.
Professor Per Sunnerhagen, Department of Chemistry and Molecular Biology, University of Gothenburg