DNA repair mystery solved

Cancer Research UK

Cancer Research UK scientists believe the final piece of the picture of how cells fix a severe type of DNA damage - thereby reducing the chances that the cells become cancerous - will fall into place tomorrow (Friday 27 January 2006) when they publish their latest findings in the journal Cell*.

Professor Steve Jackson, based at Cambridge University, discovered the first component of one particular DNA repair process over ten years ago. More pieces were found, and eventually scientists thought they had the whole process mapped out. But recent evidence came to light that suggested there was still one bit missing. Now Prof Jackson has finished what he started by discovering a new molecule that completes the picture.

The molecule is called XLF** and while it may have a role in causing cancer, it can possibly also be targeted by new cancer treatments - for example, blocking the action of XLF in cancer cells could ‘soften up’ the cells and allow radiotherapy to deliver more easily a knockout blow.

Prof Jackson said: “You could say we went fishing. We know molecules in these processes tend to bind together in order to work, so Peter Ahnesorg - a PhD student in my laboratory - used an established component of the repair pathway as bait and cast it into a sea of proteins. Then he pulled out the bait and examined what was stuck to it.

“As well as catching the usual debris and old boots, we had what looked like a real fish, a molecule that hadn’t ever been studied before. And now we’ve confirmed it is, in fact, the missing part of this jigsaw.”

DNA, the holder of genetic information, is made up of two complementary strands. If one strand gets damaged, the cell can generally work out how to fix it by using the remaining strand as a template. Double strand breaks are harder to repair and can lead to mutations and possibly cancer if they go unmended. One way of repairing double strand breaks is called non-homologous end joining, and it is crucial for protecting cells. This is the pathway that Prof Jackson has been studying.

Professor John Toy, medical director at Cancer Research UK, said: “Cells have a number of complicated processes to repair damaged DNA. This is necessary in protecting cells from the kinds of mutations that sometimes cause them to become cancerous. Researching DNA repair helps us enormously to gain a better understanding of why people get cancer.

“We hope to exploit these processes in cancer treatment. Most types of chemotherapy and radiotherapy work by causing such damage in cancer cells. The XLF molecule may complete our understanding of this DNA repair process, and the new knowledge about this protein can hopefully be used to improve cancer therapy.”

ENDS

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Notes to Editor

* Cell, Volume 124 Issue 2 - published 27 January 2006 ** XLF: XRCC4-like factor

The authors of the Cell paper are Peter Ahnesorg, Philippa Smith and Professor Steve Jackson.

Prof Jackson is head of Cancer Research UK laboratories in the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge.

DNA non-homologous end-joining (NHEJ) is one pathway that cells have for repairing double strand breaks. The other is homologous recombination.

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