HOUSTON – (May 1, 2007) - A protein called RecQ takes on a totally opposite function in the bacteria Escherichia coli to the one it fulfills in yeast and in humans, indicating that people seeking to understand the role of different forms in human cells and disease need to consider both possibilities, said researchers from Baylor College of Medicine in a report in the current issue of Molecular Cell.
Humans have five forms of this particular protein, and three are associated with syndromes that predispose people to cancer, said Dr. Susan Rosenberg, professor of molecular and human genetics at Baylor College of Medicine. Two of the forms are not associated with cancer syndromes.
Other organisms have forms of this protein in varying numbers, said Rosenberg. For example, E. coli has only one. All forms appear to be very similar, no matter what the organism. When proteins are found in a variety of organisms, they are called conserved.
"It was thought that because these were so well conserved, they should do more or less the same thing," said Rosenberg. However, research in her laboratory showed this was not the case.
In yeast and one of the human forms of a protein called RecQ actually works to help unzip DNA strands when chromosomes repair DNA damage using a process called genetic recombination. In this kind of repair, one chromosome aggregates with a partner chromosome—usually its twin chromosome following DNA replication—and then disaggregates following repair. If the repair aggregates are not unzipped, the chromosomes can't separate for reproduction. The yeast and human Werner syndrome enzymes helps prevent the buildup of unwanted intermediates of aggregated chromosomes that can actually kill the cells if not unzipped.
When that protein is lacking, the intermediates buildup and the cells die. However, while many people think all such proteins work similarly in repair, recent work by Rosenberg and others in her laboratory demonstrates that the protein works in exactly the opposite manner in E. coli.
In yeast, she said, the protein's job is to get the two chromosomes apart. One form of the protein does this also in humans, and when this protein is mutated or missing, a premature aging and cancer-predisposition disease called Werner syndrome results. Cancer results from destabilizing the chromosomes.
"When people knock out Werner (protein), they see these intermediates piling up and the cells die from failure to resolve this," she said.
Daniel B. Magner and Matthew D. Blankschien, both graduate students in Rosenberg's laboratory, found that E.coli/RecQ promotes the accumulation of these intermediates, actually promoting the cell's death by this method.
When scientists begin considering the possible of effects of other relatives of RecQ in humans and other organisms, they should be aware of this finding and consider both possibilities when seeking to link mutations in the protein to disease, said Rosenberg.
Others who took part in the research include: Drs. Jennifer a. Lee, Jeanine M. Pennington and James R. Lupski, all of BCM.
Support for this work came from the U.S. Department of Defense Breast Cancer Research Program, the Baylor College of Medicine Mental Retardation Research Center and National Institutes of Health.
A summary of the article can be found at http://www.molecule.org/content/article/abstract?uid=PIIS1097276507001578&highlight=magner
Journal
Molecular Cell