Dramatic Genetic Consequences of Single Amino Acid Change

Researchers have found that a mutation in mice resulting in the replacement of a single amino acid in the Rad50 protein was sufficient to cause birth defects and increased incidence of cancer due to accumulated errors in DNA metabolism. The finding was reported in the September 1, 2002, issue of Genes & Development.

Rad 50 is one of several proteins involved in various aspects of DNA metabolism, including the cellular response to DNA damage, DNA recombination, and the maintenance of chromosome ends (telomeres). As mutants completely lacking Rad50 do not survive, investigators from the University of Wisconsin Medical School (Madison, USA; www.wisc.edu) developed a mouse model with a point mutation in the Rad50 gene that resulted in a single amino change in the protein.

The Rad50-mutant mice displayed partial embryonic lethality, with the viable mice being only about half normal size and having severe testis and bone marrow cell attrition, which caused a large number of the mice to die by three months of age due to the severe anemia that resulted from progressive bone marrow depletion. Longer-lived Rad50-mutant mice exhibited a predisposition to lymphoma development due to a general inability to maintain the integrity of their genome.

This study demonstrated that a single amino acid change in Rad50 had far-reaching effects on the accurate transmission of genetic information from one cell generation to the next, resulting in an impaired ability to maintain stem cell populations and a predisposition to cancer. Extrapolating from mice to humans, it may be that even subtle genetic changes, such as a single amino acid substitution, may underlie cancer susceptibility in the human population.



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