It's all in the details
News and Views, december 2011
Ever asked a scientist when his research will be finished? No doubt the answer was: never! There is always more to learn. This also holds true for the 'mismatch2model' research consortium that is studying the repair of DNA mismatches. As a result of decades of meticulous experimenting, the outline of the repair process is known, the steps have been determined, the players identified and bits and pieces of the mechanism elucidated. Still the consortium wants more detail. Why? The following example will provide the answer.
Every long journey starts with a first step, as does the repair of DNA mismatches. And this first step consists of the recognition of the mistake in the DNA. When the protein MutS identifies such a mistake, it binds and bends the DNA. This also changes the shape of the protein and recently mm2m showed that MutS can then be switched on and off by two small molecules, magnesium and ATP (News & Views, September 2011). The switched-on MutS then attracts a second protein to the site, MutL. Together, these proteins initiate the repair process (a graphical representation of the complete repair pathway is on page 5 of the brochure 'Maintaining our Genetic Code').
So far, so good. But the results from different research groups started to contradict. Some groups claimed that MutS remained bound to the DNA mismatch after being switched on by ATP, while other groups claimed that MutS releases the mismatch and slides away along the DNA. Science hit deadlock. It was crucial to know which claim was correct, since MutS needs to let go of the mismatch to be able to start the actual repair reaction. Until recently, the available assays allowed researchers to visualize either the DNA or the ATP molecules. For a conclusive answer, one needed to 'see' both.
Therefore the mm2m consortium together with collaborators developed a new approach, combining a state-of-the-art technique, called native mass spectrometry, with a newly developed mathematical algorithm. This allowed them to directly detect MutS bound to both DNA and ATP. Their results provided the answer to end the deadlock. As is often the case, both apparently contradictory claims were partly correct. Mm2m shows not one but two ATP molecules are needed to switch on MutS. The first ATP is used to 'verify' that MutS is bound to a DNA mismatch. The second ATP then causes a change in the shape of MutS, releasing the mismatch and allowing MutS to slide along the DNA.
Understanding the mismatch repair mechanism in great detail is essential for drawing up a dynamic and predictive model, the ultimate goal of the mismatch2model consortium. So if you ever think about asking a scientist when his research is finished, think again. Science will never be finished!