Managing the team
If you ask the managing director of a successful company what keeps their business running smoothly, a common reply will be ‘good communication and teamwork’. Scientists are finding out that in the business of mismatch repair, similar rules apply.
Good managers know the value of each of their team members, but sometimes it takes an unexpected absence to reveal which employees you really can’t do without.
This is how researchers investigate the function of proteins in our bodies. In an experimental system - for example, yeast or bacteria cells that can easily be grown in a laboratory - they make a small change, known as a mutation, in the DNA code that tells the cell how to make a protein correctly. The scientists then study how important cellular processes are affected by changing that protein.
These mutation studies are teaching us a lot about the team of proteins that normally keep mismatch repair in business: each protein makes a unique contribution, if it is mutated there isn’t another than can step into its shoes. Scientists say there is virtually no ‘redundancy’ among the mismatch repair proteins.
So, if each employee has a unique role, how do all the elements of the business fit together? The key is communication. For example, in the business world the sales department, the warehouse, and the dispatch team have to talk and ensure someone is making the delivery. In the cellular world, communication is often achieved by direct contact between proteins. The 3D shape of a protein will determine which other proteins it can interact with - for example, some proteins have intricately shaped docking sites to which only one or two specific partners can bind. Also, proteins can change the shape of these docking sites, for example after binding to a DNA mismatch. In this way a specific message can be relayed from protein to protein, in the correct order and only when necessary.
Researchers have explored the value of communication among mismatch repair proteins by making mutations that allow a protein to do its own job but prevent it from interacting with another protein, by changing a small part of its shape, for example. They found that these mutations stop the whole system from working properly – so repairing DNA really is a team effort.
Some of the mutations in mismatch repair genes that cause Hereditary non-Polyposis colorectal cancer (HPNCC) (see ‘Mistakes in the menders’ [LINK]) have the consequence that the proteins can no longer correctly pass the signal for ‘mismatch detected’ to the other proteins of the repair team. In cells with these mutations, DNA mismatches will remain uncorrected and will result in tumour formation. Therefore, those communication skills really are vital.
Mary Muers