When cells lacking both p53 and having defective end-joining proteins fail to repair chromosome breaks, the breaks are replicated along with the chromosome during cell division. The broken ends join to broken ends on other chromosomes, causing cancer-initiating translocations. As chromosomes keep breaking, fusing their broken ends, and replicating, gene amplification results as extra copies accumulate.
Alt's more recent work is exploring further mechanisms of genomic stability in cancer. One mechanism involves H2AX, a structural protein that helps ensure that double-strand DNA breaks are properly repaired by the end-joining proteins. When p53 is also absent, loss of even a single copy of the H2AX gene can lead to translocations. "If you eliminate H2AX and P53 in mice, they get all sorts of cancers lymphomas, solid tumors, you name it," Alt says. Interestingly, simply reducing H2AX activity is enough to cause genomic instability. "You can't just think that a tumor suppressor gene has to be completely mutated or gone to contribute to cancer," he says. "We need to think in a new way about tumor suppressive genes, particularly those involved in genomic stability." H2AX is a prime candidate for further study, because it maps to a region of human chromosome 11 that is altered in a large percentage of human cancers.
A second mechanism, again drawing on Alt's work in immunology, is class switch recombination. This gene-reshuffling tool is used by the immune system to instruct an antibody where to go in the body and what strategy to use in fighting a pathogen
Contact: Susan Craig
Children's Hospital Boston