Sci. Aging Knowl. Environ., 4 September 2002
Minor mutation hamstrings DNA-guarding protein
Key Words: Spo11 Nbs1 hematopoietic stem cells
Abstract: Small errors can be disastrous: Hit a golf ball just a few millimeters off the club's sweet spot and you'll be taking your next shot from the weeds. Similarly, a subtle defect in a DNA repair enzyme triggers a mass suicide of stem cells and boosts the risk of cancer in mice, according to a new study. The finding reveals that even minute changes to the proteins that police DNA can lead to disaster.
The DNA-protecting protein in question, Rad50, is part of a trio of proteins called the Mre11 complex that checks for breaks in DNA strands. Uncorrected, such fractures can trigger a cell to kill itself or lead to genetic rearrangements that spur cancer. Once Mre11 detects damage, it halts cell division and teams with other proteins to mend the injury. Scientists have shown that mutations in the Rad50 gene impair DNA repair and reproduction in yeast, but their efforts to untangle the gene's contribution in mammals have encountered an obstacle: They can't observe the consequences of disabling Rad50 because removing the gene from mice is lethal.
To sidestep that problem, Bender and colleagues engineered mice to carry a variant of the Rad50 gene that renders yeast inordinately susceptible to DNA-damaging chemicals. To the researchers' surprise, cells from the mice grew normally in culture. However, the mice were stunted, and most perished within 3 months from severe anemia because blood stem cells in their bone marrow were dying. Animals that did survive often fell victim to cancer, which suggests that their DNA was taking a battering. The researchers found that cells from the mice had more chromosome breaks than those from normal animals.
The data suggest that tweaking Rad50 allows the accumulation of ruinous DNA damage. "Very subtle defects at a cellular level can play out with impressive pathology," says molecular biologist John Petrini of the Memorial Sloan-Kettering Cancer Center in New York City, a co-author of the paper. Hardest hit are tissues such as bone marrow that develop from a few stem cells. The death of a stem cell in such a tissue cancels out a greater fraction of cellular progeny than would be lost in tissues with many stem cells, such as the intestines.
The study confirms that the Mre11 complex is vital for keeping chromosomes intact, a result that might "help us understand how the early events in cancer take place," says molecular biologist Tanya Paull of the University of Texas, Austin. Normal Rad50 and the mutant version tested in the study differ in only one amino acid, notes biophysicist John Tainer of the Scripps Research Institute in San Diego. As scientists hunt for mutations that addle DNA repair proteins and that might make people susceptible to cancer, they might overlook such an apparently trivial change, he says. The results emphasize that a small and seemingly innocuous alteration can wreak genetic havoc, he says: "We need to look carefully for single-amino-acid changes to see how they can disrupt repair pathways." Keeping such nuances in mind might give cancer researchers a better shot at hitting their target.
C. F. Bender, M. L. Sikes, R. Sullivan, L. E. Huye, M. M. Le Beau, D. B. Roth, O. K. Mirzoeva, E. M. Oltz, J. H. J. Petrini, Cancer predisposition and hematopoietic failure in Rad50S/S mice. Genes Dev. 16, 2237-2251 (2002). [Abstract] [Full Text]
Citation: M. Leslie, Totally Rad. Science's SAGE KE (4 September 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/35/nw123
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