Elusive Chromosomal "Ignition" Identified By Salk Scientists
La Jolla, CA – Before the engine that drives cell division goes into gear, it must receive a biological spark from its genetic machinery to set the process in motion. In the current issue of the journal Science, researchers from The Salk Institute for Biological Studies say they have identified that "ignition" point on a human chromosome. Their findings should further understanding of how cell division is normally controlled and how it might be brought back under control in cancer cells.
"This discovery is fundamental to understanding how cell division gets started in humans and ultimately could help us figure out what goes wrong when the process goes awry, as in cancer," said Geoff Wahl, Salk professor and principal investigator of the study. Wahl noted that the nature, and even the existence, of specific "ignition" points on mammalian chromosomes has been hotly debated, although their counterparts in single-cell organisms were defined as early as twenty years ago.
Because of the large size of the human genome, cells use hundreds of thousands of replication ignition points during each round of the cell division cycle. Nevertheless, it was not clear how the cells choose the right place to begin the duplication of their DNA. "For years, there have been two camps," according to Wahl. "One camp thought that any stretch of DNA could function as a starting point, if it were placed in an appropriate context, and there was some evidence supporting that view. The current study, however, provides the first definitive evidence that replication requires information that is embedded in a specific DNA sequence."
In the Science study, Wahl's team examined a particular stretch of DNA, named IR (for initiation region). Preliminary studies had shown that DNA duplication started somewhere within IR, and Wahl's group sought to test whether duplication depends on IR itself or on its surroundings.
Using genetic "scissors," the investigators clipped IR out of its normal location and moved it into a place where replication does not normally initiate. DNA duplication did indeed start within IR at the new location. To show that duplication was triggered by something within IR itself and not by its new surroundings, the researchers snipped out small fragments within the transferred IR. These snips destroyed IR's capacity to trigger replication.
"It was a straightforward approach that hadn't been tried before," said Mirit Aladjem, a postdoctoral fellow in Wahl's laboratory and lead author on the study. "Many people in the field were doing biochemical experiments, but using a genetic approach allowed us to demonstrate that duplication actually depends on this specific segment of DNA."
The investigators hope that finding the ignition points for DNA duplication will open the door to studies of how normal and cancer cells use these points to regulate duplication of their DNA.
Salk co-authors include Luo Wei Rodewald and John L. Kolman. The research was supported by the National Institutes of Health and the G. Harold and Leila Y. Mathers Charitable Foundation. Aladjem was supported by fellowships from Human Frontiers Science Project Organization and is currently supported by the Leukemia Society of America.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution conducting basic science research dedicated to the improvement of human health and improving the quantity and quality of the world's food supply.
Its two main fields of concentration are neuroscience and molecular-cellular biology and genetics.