Article: 'Genetic Network' Guards Against Lethal DNA Damage

Source: Johns Hopkins Medical Institutions
Posted: March 13, 2006
'Genetic Network' Guards Against Lethal DNA Damage

The discovery in yeast cells of a genetic network that guards against lethal
DNA damage is a first step in the creation of a database of disease-causing
combinations of mutated human genes, according to researchers at The Johns
Hopkins University School of Medicine led by Jef. D. Boeke, Ph.D. In a
report in the March 10 issue of Cell, the Hopkins team described a genetic
network that is necessary for ensuring genomic stability in yeast. This
study also identified previously unrecognized genes critical for maintaining
DNA integrity and novel functions for well-known genes.

"A lot of human diseases are caused by multiple gene mutations that are
difficult to identify," said Boeke, who is a professor of molecular biology
and genetics and director of the High Throughput Biology Center at the
Hopkins School of Medicine.

The yeast cell is an excellent model for this kind of study because 25
percent of human disease genes are also found in yeast, according to Boeke.
Therefore, the discovery of this network of genes could help to identify
mutations whose combined deleterious effects cause human diseases, including
cancer and neurodegeneration, as well as aging.

"The interactions we discovered in yeast could also help researchers select
the human versions of these genes suitable as targets for the development of
new, more targeted and less toxic cancer therapies," Boeke said.

The goal of the Hopkins study was to identify pairs of genes that, while
different, play redundant roles in governing genomic integrity in yeast
cells, filling in for each other when one of the genes is mutated or
deleted. Such redundancies ensure that each task in the network of
biochemical reactions governing DNA stability is accomplished, Boeke noted.

Based on the data from this study, the investigators were able to separate
the genes governing the stability of yeast DNA into 16 modules, or
mini-pathways of genes, based on these genetic interactions, which are
called synthetic fitness or lethality interactions. Synthetic lethality is a
phenomenon in which two mutations that are not individually lethal cause
cell death when combined. Specifically, the Hopkins team identified 4,956
interactions among 875 genes involved in DNA repair, DNA replication, the
halting of replication and cell cycle progression by "checkpoints" so that
damaged DNA can undergo repair, and responses to oxidative stress necessary
for reducing the intracellular levels of highly reactive molecules that bind
to and damage DNA.

The yeast has about 6,000 genes, of which about 1,000 are essential to
survival and 5,000 are not, Boeke said. Specifically, 1,000 of the 5,000
non-essential genes are important enough so that the yeast grows slowly if
any one of them is absent. And any of the 4,000 other genes can be deleted
from the cell without interfering with the cell's growth.

Full Text at ScienceDaily
http://www.sciencedaily.com/releases/2006/03/060313183329.htm

Posted by
Robert Karl Stonjek


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