BioWorld International Correspondent

LONDON - The discovery of a key molecule in the DNA repair pathway could hasten the day in which cancer patients can undergo profiling to find out the best way to treat their particular tumor.

The molecule, called XLF, is the final missing piece in a jigsaw puzzle made up of proteins that take part in the repair of breaks in double-stranded DNA. Now that scientists have all the pieces, they feel confident that they will be able to work out how the pathway operates, and - importantly for patients - how to interfere with its components in order to improve cancer treatments.

Steve Jackson, head of the Cancer Research UK laboratories at the Gurdon Institute in Cambridge, and professor of biology at the University of Cambridge, told BioWorld International: "This area of research may, in the longer term, help us to come up with better treatments for cancer. We know that there are differences between cells from different cancers and from different patients, in how they respond to radiotherapy and chemotherapy. Some of these differences may reflect underlying variations in the DNA repair capacity of different patients or different cancers. This may, one day, make it possible to tailor therapy to the individual."

Jackson and his colleagues want to study XLF and the other proteins involved in the repair of double-stranded breaks in DNA, in order to understand how they work, and how they are connected to the control of the cell cycle and apoptosis.

The DNA repair pathway that mends double-stranded breaks also contains several "very exciting" drug targets, Jackson said. KuDOS Pharmaceuticals, of Cambridge, UK, which Jackson founded, has just been acquired by AstraZeneca plc, of London. Jackson said: "KuDOS will be actively pursuing ways of making small-molecule drugs that target DNA repair pathways, with the aim of enhancing existing therapies. We also have evidence that some inhibitors of these molecules could work as stand-alone treatments."

A report of the discovery appears in the Jan. 26, 2006, edition of Cell in a paper titled "XLF Interacts with the XRCC4-DNA Ligase IV Complex to Promote DNA Nonhomologous End-Joining." The first author is Peter Ahnesorg.

More than 10 years ago, Jackson and his collaborators identified the first component of the DNA repair pathway known as nonhomologous end-joining (NHEJ), which is of great interest to cancer scientists. DNA damage is a regular occurrence in normal cells. If it is not detected, or not repaired properly, mutations can result, and those might allow cancer to develop. In addition, treatments such as radiotherapy, and many chemotherapies, work by inducing double-stranded breaks in DNA, which the cell must repair by NHEJ if it is to survive.

Jackson and his team therefore have been studying how cells detect double-stranded breaks and how they repair them. He said: "If we can understand this pathway, we might be able to modulate its components with drugs, and make chemotherapy and radiotherapy work more effectively."

Until a few years ago, the team thought that all components of the NHEJ pathway had been identified. But a team led by Penny Jeggo at the University of Sussex identified a patient whose cells were unable to carry out NHEJ, although the patient had all the proteins that researchers knew of.

"So everyone knew that this patient must have been defective in something else," Jackson said.

Ahnesorg, Jackson's Ph.D. student, looked for proteins that interacted with all the known proteins in the NHEJ pathway, using a yeast two-hybrid screen. Jackson said: "You could say we went fishing. 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. This molecule was XLF, and it is the missing part of the jigsaw."

In the same issue of Cell, an international team of mainly European researchers described the identification of the same gene, which they call Cernunnos, in five patients. The individuals had growth retardation, microcephaly and immunodeficiency, as well as increased sensitivity to radiation. The cause, the team showed, was a DNA repair defect caused by a fault in the Cernunnos (XLF) gene.

Interestingly, Jackson explained, the reason why people with a DNA repair defect often present with immunodeficiencies is because the NHEJ pathway plays an important role in the "cutting and pasting" of DNA that takes place in order to generate diversity of antibodies and T-cell receptors, which is essential for these proteins to recognize foreign antigens.

No Comments