Nov. 12, 2001 Simultaneous reports by two teams at The Scripps Research Institute (TSRI), led by Professor Paul Russell, Ph.D., and Associate Professor Clare H. McGowan, Ph.D., identify the "resolvase" enzyme that may be responsible for generating genetic diversity during sexual reproduction and could be a target for improved anti-cancer therapy.
In the current issues of the journals Cell and Molecular Cell, the researchers have published papers that describe Mus81, a resolvase enzyme of the fission yeast Schizosaccharomyces pombe, and its human analog.
Resolvase is essential for a crucial step in DNA recombination, says Russell, because it is the molecule that allows two chromosomes to cross over. "It is one of the most important enzymes involved in genetic recombination," he says.
Genetic recombination occurs in the process of meiosis, when chromosomes from the mother and father become paired. The aligned chromosomes break and DNA strands from both chromosomes become intertwined at the point of the cross-over. At the molecular level, this combining happens at what is called a "Holliday junction," where the strands of DNA literally cross one another.
However, the DNA must at some point be uncrossed by cutting across the Holliday junction in the last crucial step in genetic recombination. This is the responsibility of resolvase enzymes. The final product of this process is a pair of new chromosomes that have genetic material from both parents.
"[Resolvase] is the molecule that allows children to inherit a unique mixture of traits from mother and father, without it we wouldn't have the infinite range of genetic combinations that makes us all different," says McGowan.
It has long been known that there should be such enzymes, and several examples from other organisms, such as bacteria, have been around for years. And for years, scientists have searched for the resolvase gene in eukaryotic cells, such as humans and yeast, which have linear chromosomes packaged in a nucleus. Until now, none has been found.
Russell and his colleagues showed that Mus81 is an essential component of the resolvase enzyme in yeast cells. Mus81 is structurally unrelated to bacterial resolvases. In a related work, McGowan's study demonstrated that a human analog of the Mus81 protein also has resolvase activity.
The identification of a human resolvase may have a profound effect on cancer therapy because the enzyme also has an important role in cell replication.
When cells are replicating their DNA prior to division, they have mechanisms to sense if the DNA is damaged. When the DNA is damaged, a cell's replication machinery will stop, spontaneously back up and form a Holliday junction. Resolvase recombines DNA strands at Holliday junctions and this allows the replication machinery to bypass the damaged DNA.
Cancer cells are often defective in the mechanisms that sense damaged DNA. Russell and McGowan envision that treatment of tumors with chemotherapeutics that damage DNA, combined with rational targeting of resolvase activity, could be a highly potent cancer treatment.
This research is also another vindication of fission yeast as a model organism for human biology. Resembling humans, S. pombe cells reproduce sexually through meiosis and have a similar cell cycle. Because of the ease of manipulating yeast genetically and because of their uncanny similarities, S. pombe is a good model system for studying the human cell cycle.
"S. pombe has contributed enormously towards understanding the human cell cycle and towards advances in the treatment and understanding of cancer," says McGowan.
The research article "Mus81-Eme1 Are Essential Components of a Holliday Junction Resolvase" is authored by Michael N. Boddy, Pierre-Henri L. Gaillard, W. Hayes McDonald, Paul Shanahan, John R. Yates 3rd, and Paul Russell and appears in the November 16, 2001 issue of Cell.
The research article "Human Mus81-Associated Endonuclease Cleaves Holliday Junctions In Vitro" is authored by Xiao-Bo Chen, Roberta Melchionna, Cecile-Marie Denis, Pierre-Henri L. Gaillard, Alessandra Blasina, Inez Van de Weyer, Michael N. Boddy, Paul Russell, Jorge Vialard, and Clare H. McGowan and appears in the November, 2001 issue of Molecular Cell.
The research was funded by the National Institutes of Health, by The R.W. Johnson Pharmaceutical Research Institute, and by the Janssen Research Foundation.
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