Dealing with damaged DNA

The DNA inside your cells is under an enormous amount of strain, every second of the day. It is constantly being pulled, twisted, folded, squashed and stretched – and all it wants to do is carry on doing its absolutely essential job of keeping you alive. In patients with Fanconi anaemia, a form of blood cancer, a set of proteins which is essential for keeping the DNA intact whilst it undergoes all this stress are faulty, leading to damage to the DNA molecule that eventually leads to the development of cancer. Scientists have known for some time that these proteins play a critical role in preventing DNA damage, but precisely how they work has remained elusive – until now. A recent study by Wojciech Niedwiedz’s lab, published in Molecular Cell, shows some critical insights into why patients with Fanconi anaemia develop the disease. Martin Larke explains more.

Your body isn’t just one big lump of flesh and bone, it consists of thousands and thousands of tiny individual cells. Inside each of these cells is a long string of chemical letters or “bases” known as DNA, which is essentially a bit like a huge book containing all the information required to make a human.

As your body grows, your cells get bigger and eventually divide to form two cells. As part of this division process the entire DNA string is copied in a process called replication, just like making two copies of a book by copying from an original.

Your cells are very clever, and in the same way that you might look up a topic in an book and copy down some specific information you need to know, your cells can access and make copies of smaller sections of the DNA, known as genes. This process is called transcription.

But this presents a problem for your cells; what happens if DNA replication and transcription happen at the same time?

When the two processes collide on the same piece of DNA, this can damage the DNA molecule and cause it to break. This is a bit like what would happen if you were trying to copy one page from a book whilst at the same time someone else was making a copy of the whole book by turning over the pages: as a result of the two things happening at the same time, neither task would get done properly, and the book would probably end up damaged.

When this happens inside your cells scientists call it replication stress and it can cause so much damage that the information in the DNA gets jumbled up and rearranged, which prevents the genes from functioning properly. The instructions on how to make a normal cell are damaged, which is the first step along the path to developing cancer..

But it’s not all bad – your cells have developed ways of helping to prevent this damage from occurring, and one very important way of doing this is through the action of a family of proteins we call FANCs.

Fanconi anaemia is a disease that occurs when the FANC proteins do not function correctly, leading to replication stress which damages cells in the bone marrow. This results in anaemia (low levels of red blood cells) and a much higher risk of developing cancer, often in childhood.

However, although we know FANC proteins play a critical role in preventing the development of cancer, little is known about how they actually work and so scientists in the WIMM have been studying these proteins in detail to find out more.

Recently, a team led by Dr Wojciech Niedzwiedz has shown that FANC proteins are found in places where DNA replication and transcription are happening at the same time, and part of their job is to ease the stress on the DNA.

To investigate this further, the team then used a chemical that prevents transcription in special type of cell that does not have a full set of working FANC proteins. This allowed them to show that one protein in particular (FANC-M) acts by easing tension in the DNA like untwisting a rope, preventing breaks from happening and allowing replication and transcription to occur side by side.

Published in Molecular Cell late last year, these findings are an important discovery in the cancer research field. By gaining a greater understanding of precisely how the FANC proteins work to protect our DNA, scientists at the WIMM hope that this knowledge can be used to develop more effective treatments for the thousands of patients, many of them children, who suffer from this debilitating condition.

Post edited by Bryony Graham and Wojciech Niedzwiedz.