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!