ocess called non-homologous end joining (NHEJ), decided to probe whether DNA repair proteins are involved in complicon formation. They began by knocking out a major DNA repair mechanism in mice, effectively creating mice that lack one of two proteins central to NHEJ. Mice lacking NHEJ normally die before birth, because the cellular system for detecting high levels of DNA damage triggers programmed cell death, also called apoptosis. To keep the mice alive longer, the researchers also knocked out the gene for p53, which is an important component of the DNA damage detection system.

"When we eliminated the p53 protein, the mice survived fine until after birth," said Alt. "However, after only a few weeks they began to develop pro-B cell lymphomas, from which they died." Pro-B cell lymphomas are tumors that arise when cells of the immune system, called B cells, proliferate at an immature stage of development.

The researchers found that the lymphomas in these mice showed amplifications of genomic regions, or loci, containing two genes c-myc and IgH-- involved in B cell development. These amplifications somehow arose from complicons produced when the mouse chromosomes 12 and 15 underwent translocations.

To understand how complicons gave rise to these lymphomas, the scientists decided to test whether the translocations depended on a DNA-snipping enzyme called RAG. This enzyme is critical for joining and recombining genes in the normal development of B cells.

"We thought a requirement for RAG was a good possibility, because we knew that the IgH gene locus was a target for RAG," said Alt. "Also, it's been long proposed that RAG-induced chromosome breaks can lead to translocations that cause amplifications in other kinds of tumors."

The researchers demonstrated that RAG is required for complicon formation by making "triple-knockout" mice that lacked RAG, p53 and XRCC4, a protein involved in DNA repair. The triple-k
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
27-Jun-2002

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