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A Nobel for DNA Repair

This year’s Nobel Prize in Chemistry goes to Tomas Lindahl of the Crick Institute, Paul Modrich of Duke/Howard Hughes Medical Institue and Aziz Sancar of UNC – Chapel Hill, for mechanisms of DNA repair. Here’s the press release, and here (PDF) is the detailed scientific background from the Nobel committee. This is not a prize that registered on the most comprehensive list of odds for the prize (although another DNA repair response possibility did). It’s a good award, though, because this is a critical process for life, and at one point no one thought that any of it existed.

Once DNA was identified as the molecule of heredity (which was well before Watson and Crick famously worked out its structure), it was clear that it somehow had to be an unusually conserved substance. If there was a complete blueprint for every cell being carried around, and there certainly was, then it had to be kept as free from error as possible. (If the error rate were above a certain limit, you’d expect life itself to not be possible). So one thought was that DNA must be an exceptionally stable molecule, that evolution had ended up selecting it for just that reason.

That hypothesis did not hold up for long. Outside the cell, isolated DNA was very easy to degrade (a vigorous stirring would break it into pieces). It also turned out to be photosensitive, temperature sensitive, and all-sorts-of-other-stuff sensitive (as demonstrated by Lindahl in his work on “DNA decay”), and that meant that living cells (1) must have mechanisms to repair DNA damage and (2) must spend a substantial amount of time and energy on them. And so they do. There are a lot of ways that DNA can accumulate damage and errors, and there are a lot of ways that it gets checked and repaired.

One of the most common of these occurs on exposure to ultraviolet light from the sun. The DNA base thymine is particularly sensitive, and does a 2+2 reaction to form a four-membered ring compound, a thymine dimer. These tend to stop essential DNA-reading enzyme machinery in its tracks, and experiments in the 1960s and 1970s showed that cells dealt with this problem by actually snipping out these sections of DNA and replacing them (nucleotide excision repair, or NER). Sancar worked out how the three enzymes in this process work together, cleaving the DNA up- and downstream of the dimer, synthesizing a replacement, and stitching it back in.

NER also gets used to fix some other types of DNA damage, but there’s another mechanism to fix thymine dimers as well. That’s the photolyase system, which was actually the first DNA repair mechanism noted. Recovery of cells from ultraviolet light damage had been found, oddly, to depend on visible light being available in plants and bacteria. Sancar isolated the enzyme responsible (photolyase) while he was still in grad school, and years later went back to work on its mechanism as well. These enzymes harvest light to be able to break a bond in the cyclobutane ring, causing it to revert back to the starting structures. Don’t try to treat your own sunburn by exposing yourself to more light, by the way – the photolyase pathway doesn’t exist in mammals.

For his part, Lindahl discovered another pathway, base excision repair. This handles less obvious problems than thymine dimers (which create an obvious lump in the DNA strand), going after individual DNA bases that have been alkylated, oxidized, or have lost an amino group. (There really are a lot of ways for nucleic acids to degrade). A whole cascade of enzyme recognize the damaged bases, yank the DNA in that region so as to flip the altered base from the inside of the helix to the outside, cleave it off, cut the DNA nearby, and patch in a replacement. It’s a multistep process, and defects in it have been shown to be associated with several forms of cancer.

Paul Modrich’s contribution was on yet another type of DNA repair, this time correcting base-pair mismatches that inevitably occur during replication. These non-Watson-Crick base pairs jump the rails of the entire DNA information coding system, and if allowed to accumulate, would lead to all sorts of mutations and messed-up transcription. Since these mistakes occur during DNA replication, the key to understanding them was the realization that there was a way for enzymes to distinguish newly synthesized DNA from older material. That’s DNA methylation, which (among other things) is used as a sort of time stamp: unmethylated stretches of DNA are freshly laid down, and there are whole suites of proteins that go over them and can bind to errors. Modrich and his group were first able to isolate the various parts of this system from bacteria, and in recent years did the same with the human enzymes, demonstrating that the whole repair process could be reconstituted ex vivo by assembling the relevant proteins and an engineered stretch of DNA with defined errors and methylation states. This process happens on one strand of the double helix only, the new part that was laid down during replication, and the methylation is key to determining which strand is the one to match to and which is the one to strip out.

It’s another complex suite of enzymes and other protein partners, and just looked over it, you can see how important DNA repair is. Evolutionarily, DNA fidelity is a very big deal indeed, with the potential to destroy every system in a living cell right from the start. So while there’s an extraordinary amount of complex enzymatic machinery to replicate DNA, there’s an even more widely varied set of mechanisms to make sure that the whole process worked correctly, and to constantly look for and repair problems that accumulate afterwards.

That makes this Nobel rather easier to explain to the general public than some of them, because (as mentioned above) such DNA defects can lead to either cell death or to a cancerous state. Defects in DNA-repair machinery are very common in many types of cancer cells, and the genomic instability of such cells is both a hallmark of their behavior and a look at what would be going on all the time were it not for all these systems working as well as they do. A large number of neurological and metabolic disorders are associated with defective DNA repair, as well as disorders of aging in general. This is an absolutely crucial part of cell biology, a subject of great scientific interest all by itself and one of huge medical importance as well, and the Nobel for it is well deserved. As usual, the only thing to add is that there have been so many other people over the last forty years who have also contributed to this vast field of study, and the hard part is just restricting such a prize to three of them or fewer. Congratulations to everyone involved!

 

30 comments on “A Nobel for DNA Repair”

  1. Isidore says:

    Thank you for the excellent summary!

  2. NMH says:

    Interesting. I know a little about PM’s lab (briefly was there as my advisor collaborated with him). Seemed like PM’s standards for publication were very high.

    What is interesting is that there are a few others who some would argue made equal contributions to the field (eg Richard Kolodner, Thomas Kunkel) who appear to have been ignored. Seemed like PM was always in a race with Kolodner, but PM usually just beat him to publication just by a little. Lu and Modrich beat Fishel and Kolodner as the first to set up an in-vitro MMR system for a publication back in the early 1980’s, for example.

    Now PM will get a life extension for getting a nobel prize, while Richard Kolodner will not. Little differences here and there can make all of the difference sometime

  3. canman says:

    Ok, I’ll be the first to bring it up so we can get over it.
    This clearly isn’t chemistry. I know that “everything is chemistry” if you look close enough, but studying and isolating enzymes doesn’t look like chemistry in my books.

    1. anon says:

      It’s catalysts carrying out chemical reactions on very large molecules. It’s chemistry.

  4. me says:

    Not chemistry.

  5. Jon says:

    It sounds like a well-deserved prize, but it does it seem to anyone else that the prizes for Chemistry and Physiology or Medicine could have been swapped this year and made a bit more sense awarded that way?

  6. lux libertas, eruditio et religio says:

    Congratulations to the winners and their scientific staffs. Great to see RTP represented again. Derek – your alma mater has done especially well the last few years.

  7. NMH says:

    I’m a little familiar with the field and the literature and I can tell you that most of the stuff from 1975 – 1995 from Sancar and Modrich is straight, old fashioned BIOchemistry. Look at PM’s papers from the 1980’s and its all about classic protein purification and characterization. Things like four-step column chromatography in a cold room to isolate a protein, then nucleotide binding assays to charcterize its function. Same with Sancar’s early work. So the question is: is protein purification and characterization chemistry?

    No, its no Georg Wittig finding a way to sythesize and alkene in a single flask.

    1. Terry says:

      Very surprised that Evelyn Witkin was overlooked. She discovered the SOS (recA/lexB) DNA repair system, which was the fundamental underpinning for the subsequent, awarded work.

  8. Erebus says:

    This should have been a physiology prize. It has everything to do with physiology and very little to do with chemistryper se.

  9. π in the Sky says:

    I really wish that there was a Nobel dedicated to biochemistry and/or biology. Is it chemistry? Sort of. Is it physiology/medicine? Sort of. DNA repair is certainly deserving of a Nobel Prize; however, I feel that presenting it under the pure chemistry banner is not quite right

  10. dude says:

    this year chemistry nobel prize was in medicine

  11. Peter says:

    Congratulate to Thomson Reuters! Another year of precise prediction!

  12. PhSH says:

    obviously should have gone to transition metal photoredox

  13. Anon says:

    Comments above on the mis-classification of Nobel Prizes between Chemistry and Medicine/Physiology are both boring and ignorant. Remember that the Nobel prizes were created around 1900, before most of these inter-disciplinary fields were even conceived. Science would never have advanced at all if it was left to such narrow-minded purists. So get over yourselves and open your mind.

  14. dearieme says:

    Rutherford was given the Nobel in Chemistry, so there’s plenty of precedent for having a wide interpretation of what Chemistry is. Though the Rutherford award may be the only one that was also a brilliant joke.

  15. Anon says:

    Since arguably the prize for medicine went for organic chemistry this year, this is one of the few times it has evened out.

  16. JPMor says:

    As for the intercrossing of discipline keep in mind the works of Marie Curie: she was awarded Nobel Prize in Physics (1903) along with her husband and Becquerel “in recognition of the extraordinary services they have rendered by their joint researches on the radiation phenomena” and later for chemistry (1911) “in recognition of her services to the advancement of chemistry by the discovery of the elements radium and polonium, by the isolation of radium and the study of the nature and compounds of this remarkable element”. We all agree she has created tremendous advances in medicine as well but was never awarded that price. Nobody else in the recent history of science can make that claim. She is the best example that all the above discipline are closely connected, now more than ever.

  17. Mike Brown says:

    Chemists hating biochemistry, why?

    1. Esteban says:

      > Chemists hating biochemistry, why?

      Heaven knows, but this is possibly the world’s least interesting squabble.

  18. Ash (Wavefunction) says:

    This year both the medicine Nobel and the chemistry Nobel went to chemistry (yes, DNA repair fundamentally involves important chemical reactions, including old school photochemical reactions, and avermectin and artemisinin are both natural products) so if this winning streak still makes people think “it’s not chemistry” I don’t know what will.

  19. Andy T says:

    @Ash, don’t forget the Nobel to physics last year too (and chemistry of course). Other disciplines aren’t invading chemistry. Chemistry is invading other disciplines.

  20. Crimso says:

    You should see the spittle-flecked rage that accompanies the occasional faculty meeting discussion of changing from “Department of Chemistry” to “Department of Chemistry and Biochemistry.” We graduate more students from our department with B.S. in Biochemistry than we do B.S. in Chemistry (a recent development, as the biochem degree is only 5 years old). I’m an Assoc. Prof., but none of my degrees are in chemistry. Can’t we all just get along?

    Naaah.

  21. Joel says:

    What would you say to swapping the chemistry and medicine awards this year? I know you’ve argued for a broader definition of chemistry, but the medicine award almost seems more like traditional 🙂 small molecule chemistry.

  22. dave w says:

    So y’all are saying that the “chemistry” prize should have been “biochemistry”, and the “medicine” one should have been “pharmacology”?

  23. Ash (Wavefunction) says:

    Andy T: Yes, that’s a good way to put it! (Also, can we have nested comments on this website?)

  24. Carbon-Silicon Bond says:

    Chemists fighting with biochemists? I though that the natural enemy of the chemist was the metallurgist.

    With the boundaries so blurred these days any classification into the Nobel categories is a bit of a crap-shoot. Excellent work has been awarded under all headings this year, but yes, if they’d all rotated on place round the table no-one might have noticed.

  25. A Nonny Mouse says:

    I note, sadly, that the great chemist and Noble prize winner Heck has died in poverty in Manila as he could not afford the drugs to keep going. A sad indictment on a sector where his work contributed so much.

  26. Chloro says:

    In fact, many proteins contained in DNA repair complexes are defective in cancer. DNA repair is essential for the accurate preservation of genetic information and to ensure the healthy functioning of cells, and a connection between aging and DNA damage has long been suspected.

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