Chromosome Copying: Salk Scientists Identify Unique Mechanism
La Jolla, CA – Before the moment of conception, living organisms experience another distinct birth – the creation of healthy eggs and sperm. Salk scientists recently obtained a peek at how genetic material is copied during the process, called meiosis, that produces these sex cells.
A fuller understanding of meiosis is expected to shed light on the mechanisms underlying birth defects and spontaneous abortions.
"We found that DNA replication – the copying of the genetic material – appears to be jump-started in a completely unexpected manner in meiosis," said Susan L. Forsburg, Salk associate professor and lead author of the study, which appears in the current Nature Genetics.
Forsburg's studies took place in the model organism fission yeast, but many of the key players studied in yeast have counterparts in mammals, including humans.
As reported in the study, the Salk team examined strains of yeast with mutations in a number of genes known to be necessary for mitosis, "ordinary" cell division.
Mitosis occurs inside each of us continually, as skin or liver cells turn over, and errors in mitosis can lead to cancer.
"Because mitosis happens all the time, and meiosis is a special process that takes place at only a certain time and location, we thought there were bound to be some differences," said Forsburg. "People assumed, however, that DNA replication was probably the same in both cases. We found out this is not true at all."
Forsburg's group assembled a battery of yeast strains that, due to mutations in different genes, could not duplicate their DNA properly at temperatures above 33 degrees Celsius (slightly below human body temperature). They asked if the mutants could carry out meiosis at elevated temperatures.
Some mutants faltered, but a surprising number had no difficulties completing meiosis normally.
"What's interesting to us," said Forsburg, "is that the mutants seem to fall into two categories. Those with mutations in genes responsible for what we'd call the 'mechanical' aspects of copying DNA – the physical machinery that fashions the new DNA chain – could not complete meiosis. This tells us that this part of the process is the same in both types of cell division."
"But the mutants that can't get ordinary DNA replication going had no problem at all initiating meiosis," she added, "indicating that meiosis uses unique start switches. Our next step is to find those switches."
The other difference detected between the two types of division lies in "checkpoint" controls – the molecular monitors that ensure accurate copying and hold it up if mistakes occur.
"In complex organisms these 'oversight' mechanisms are important for preventing cancer and, during meiosis, for ensuring healthy and complete eggs and sperm," said Forsburg. "We hope that understanding them will give us some insight into preventing birth defects and spontaneous abortions."
Co-author on the study is Jeffrey A. Hodson, a research assistant in Forsburg's laboratory. The study, titled "Mitotic replication initiation proteins are not required for pre-meiotic S phase," was supported by the National Institutes of Health and the Leukemia and Lymphoma Society.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.