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Better model of deadly brain cancer

Researchers have created a mouse model that closely mimics human medulloblastoma, the most common type of childhood brain tumor. The new model, which was created by knocking out a key component of the DNA repair machinery, will aid in exploring the genetic roots of this deadly brain cancer.

The researchers, led by Howard Hughes Medical Institute investigator Frederick W. Alt, published their findings the week of April 24, 2006, in the early online edition of the Proceedings of the National Academy of Sciences. Catherine Yan, who is in Alt's laboratory at Children's Hospital Boston, was lead author of the article. Other co-authors were from Brigham & Women's Hospital, CBR Institute of Biomedical Research, Children's Hospital and Dana-Farber Cancer Institute, all of Harvard Medical School.

Although childhood cancers are rare, brain tumors are among the most common. About one out of five childhood brain tumors is medulloblastoma, an aggressive cancer of the cerebellum. Alt and his colleagues produced the mouse model of medulloblastoma by knocking out a gene called XRCC4, which produces a protein that plays an important role in stitching together the ends of broken DNA. These breaks which can occur in all cell types from exposure to radiation, chemicals, or other insults, occur specifically in the immune system when genes are snipped and rearranged to produce a vast array of antibodies. The abnormal swapping of chromosomal regions that ensues when such repair goes awry--known as chromosomal translocations--is sometimes harmless, but can contribute to cancer and other diseases.

In earlier studies, Alt and his colleagues discovered that XRCC4 is a component of nonhomologous end-joining, a process that is essential for the repair of chromosome breaks. They found that knocking out this gene in mice led to widespread death of newly generated neurons and death late in embryonic development. The researchers then combined these exper
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
26-Apr-2006


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