Rad50 and the maintenance of genome stability

August 31, 2002

Dr. John Petrini and colleagues have succeeded in creating the first mouse model of Rad50 deficiency, lending unprecedented insight into the in vivo function of this protein in maintaining genome stability and preventing cancer in mammals.

Rad50, along with two other proteins (Mre11 and Nbs1), comprise what scientists call the Mre11 complex. The Mre11 complex is an evolutionarily conserved protein complex found in both yeast and mammals, that is involved in several aspects of DNA metabolism, including the cellular response to DNA damage, DNA recombination, and the maintenance of chromosome ends (telomeres). Previous attempts to elucidate the function of the Mre11 complex in mammals have been thwarted by the embryonic lethality of null Mre11 complex member mouse mutants. Dr. Petrini and colleagues have now overcome this hurdle.

"We knew from previous work in a number of labs that mutations that completely abrogate DNA recombination and chromosome repair lead to early embryonic death. The trick here was to make a more subtle mutation, and to get a viable mouse," explains Dr. Petrini.

In choosing their Rad50 mutation, the researchers turned to previous work in yeast. Dr. Petrini and colleagues made a point mutation in the Rad50 gene that results in a single amino change in the protein. This mutation had been shown to impair Rad50 function in yeast. The scientists quickly discovered, though, that this subtle change at the amino acid level of Rad50 had serious, and unexpected, consequences for the organism.

The Rad50-mutant mice displayed partial embryonic lethality, with the viable mice characterized by a ~50% decrease in size and severe testis and bone marrow cell attrition, causing a large number of the mice to die early on (by age 3 months) due to the severe anemia that results from progressive bone marrow depletion. Longer-lived Rad50-mutant mice exhibited a predisposition to lymphoma development, which the researchers traced back to a general inability to maintain the integrity of their genome.

Interestingly, though, the genomic instability found in these Rad50-mutant mice was not the result of a biochemically detectable decrease in Rad50's ability to perform its previously characterized functions in DNA repair and cell cycle regulation - indicating that even extremely subtle alterations of protein function can exert a huge impact on the organism, as a whole.

Dr. Petrini and colleagues have demonstrated that a single amino acid change in Rad50 can have 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. This work suggests that even subtle genetic changes, like a single amino acid substitution, may underlie cancer susceptibility in the human population.

In describing future project aims, Dr. Petrini states that "One of the next steps will be to examine the tumors that arise in these animals and establish a detailed genetic picture of the sorts of chromosome changes that occurred en route to malignancy. I predict we'll find some interesting and potentially important new cancer causing genes."

Cold Spring Harbor Laboratory

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