Nature 456, 453-454 (27 November 2008) | doi:10.1038/456453a; Published online 26 November 2008
Robert M. Brosh, Jr
Genomic instability often underlies cancer. Analyses of proteins implicated in a cancer-predisposing condition called Bloom’s syndrome illustrate the intricacies of protein interactions that ensure genomic stability.
Bloom’s syndrome, which is characterized by severe growth retardation, immunodeficiency, anaemia, reduced fertility and predisposition to cancer, is caused by mutations in the gene BLM. At the cellular level, the hallmark of this genetic disorder is a high rate of sister-chromatid exchange — the swapping of homologous stretches of DNA between a chromosome and its identical copy generated during DNA replication
Robert M. Brosh Jr is in the Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, Baltimore, Maryland 21224, USA.
2. “The BLM protein complex consists of several components, much like a mousetrap. With all the parts properly assembled, the mousetrap will operate efficiently and catch the mouse. In this case, a DNA structure called a double Holliday junction is caught in the BLM complex. Xu et al. and Singh et al. report the discovery of a component of this complex, RMI2, which stabilizes and orchestrates the action of the BLM complex, ensuring resolution of the double Holliday junction, and so promoting chromosomal stability.”
3. “As for the significance of RMI2 to the BLM complex, for analogy let’s imagine a mousetrap. It contains several components, including a spring, a platform, a hammer, a hold-down bar and a catch. Omit certain components of the trap, and the device may still operate, albeit less efficiently. With all of the components in place – including those with primarily structural roles such as the hold-down bar and the platform – the trap is most likely to catch the mouse. Returning to the BLM complex: through its interaction with RMI1, RMI2 allows the ‘BLM–Topo-3alpha device’ to assume optimal stability and configuration so that it can efficiently catalyse the splitting of the double Holliday junction, and so prevent the escape of deleterious DNA structures that would lead to crossovers (Fig. 1). RMI2 therefore seems to have an integral structural role in the BLM–Topo-3alpha device by orchestrating its action.”
This is made relevant by Behe’s observation that “Darwinian scenarios, either for building mousetraps or biochemical systems, are very easy to believe if we aren’t willing or able to scrutinize the smallest details, or to ask for experimental evidence. They invite us to admire the intelligence of natural selection. But the intelligence we are admiring is our own.”