Mending the bridge: mismatch repair to the rescue
It is a classic movie sequence: the hero comes to a ravine spanned by narrow bridge of wooden planks suspended between two ropes, as he runs across he loses his footing where a plank is missing, but manages to cling on with one hand and scrambles to safety. Almost every cell in our bodies contains a delicate double-strand like that bridge – our DNA. And if the planks aren’t joined correctly there can be serious consequences.
The planks that link the two strands of a DNA double helix are called base-pairs.
A base on one strand needs to match its correct partner on the other strand in order for form a firm joint:
an ‘A’ base pairs with a ‘T’ base and a ‘G’ base pairs with a ‘C’ base. This base-pair rule is what gives DNA its remarkable ability to
be copied accurately over and over again. The two strands can be pulled apart and a new strand assembled on each of the original stands.
For example, an A on one original strand triggers a T to be added to the new strand; in the same position on the other original strand there will be a T, so an A is added to the new strand. Therefore two identical double-stranded DNA ‘bridges’ are made from one. This process is called DNA replication and it provides a complete copy of the genetic information for each new cell that is made – like photocopying an instruction manual.
We all grow by our cells dividing – one cell becomes two, two become four, and so on – and given that the more than 50 trillion cells of an adult human come from a single fertilized egg that’s a lot of DNA replication. If a mistake is made during one cycle of replication – perhaps a C is inserted instead of a T – it might be copied the next time the DNA is replicated, and the new cells will end up with inaccurate genetic instructions. Some mistakes in DNA can alter the way cells behave and can cause them to form tumours. Therefore precise DNA replication is vital for maintaining normal health and development.
So how are mistakes prevented? The molecular machine that makes new strands of DNA is called DNA polymerase and it has a ‘proof-reading’ mechanism to check that the base it has added forms a perfect match. However, occasionally even this proof-reading fails and a mistake slips through the net. Because of the importance of making an accurate copy – keeping all the planks of the bridge intact – cells, like all movie heroes, have a back-up plan. This extra safety mechanism is called mismatch repair.
There are two main steps in mismatch repair: first, the wobbly plank – for example, an A joined to a C instead of a T - needs to be recognized; and second, repair machinery needs to be directed to the new strand of DNA so the mistake can be corrected. Scientists have discovered some of the proteins involved in these two steps and what their jobs are, but there are still more details that need to be worked out. Slowly, scientists are building up a picture of how cells are able to keep the delicate DNA ‘bridge’ in good shape. This will help to improve the understanding of the causes of it going wrong and the consequences for our health.
Mary Muers