Woop woop! Genetics has made it into the Nobels this year. The 2015 Prize for chemistry has been jointly awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar for their work in discovering the mechanisms that repair the DNA inside us all. From its discovery as the bearer of our hereditary information by Crick and Watson in 1953 right through the 1960s there had been the assumption that DNA must be an incredibly stable molecule. This had been a false assumption, though, based on the premise that, if it frequently mutated, then it wouldn’t have the stability over the generations needed for life to survive and evolve.
Lindahl was amongst the very first people to actually give this due scrutiny. He discovered that the DNA in our cells is constantly under attack from factors such as ultra violet radiation in sunlight, infectious pathogens and also from errors made during DNA replication when our cells are dividing. It wasn’t, then, as stable as thought and there must be a mechanism that somehow repaired the many faults that we all accumulate as we go about our lives.
It turned out that there were actually three main mechanisms at play. One of the weaknesses of the DNA molecule is that cytosine, one of the four bases that make up the code of our DNA, easily loses an amino group and turns into uracil. Cytosine pairs up with guanine but uracil pairs up with adenine and so this would result in a change in the code. Lindahl discovered the base excision repair mechanism which spots this defect, cuts out the offending molecules and repairs them with cytosine again. Our bodies are constantly doing this.
Modrich discovered the mismatch repair mechanism which is responsible for fixing the errors made when DNA is replicated in preparation for cell division. Every time one of our 10 trillion cells divides we need to copy all 3 billion letters of the DNA code that makes up our genome. That’s a lot of opportunities to make mistakes. Our replicative machinery is pretty damned good at maintaining the fidelity of the code but it isn’t perfect; the new mechanism was shown to reduce the error rate by a thousand fold.
Sancar was the guy who first described the nucleotide excision repair mechanism. This is the one that can repair mutations caused by exposure to UV light. This process is similar to the base excision repair mechanism but instead of cutting out just one base pair it removes the surrounding sequence as well before repairing the entire area (see below).
People who have defects in any one of these mechanisms are quite likely to develop cancer and other unpleasant diseases at some point in their lives. Knowing that these mechanisms existed was the first step to researching them in detail so that we could start to develop treatments to compensate for their absence. If these mechanisms worked perfectly then I, for one, would be out of a job. My day job as a geneticist is spent looking for and analysing the mutations that can arise when an alteration to our genetic code slips through the net. Sancar, Modrich and Lindahl were pioneers that weren’t going to accept the paradigm and provided insights that have gone on to benefit millions of people in hospitals around the world.