Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

’Genetic network’ guards against lethal DNA damage

15.03.2006


Discovery in yeast opens door to new source of information on DNA damage, repair, and cancer



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.

A major goal of the Hopkins team is to determine which of the non-essential genes interact with each other, said Boeke. All such pair-wise combinations of the 5,000 non-essential genes in the yeast genome would require about 25 million tests, he added. In the current study, 74 genes were tested in pair-wise combination with the 5,000 non-essential genes, a feat approximately equivalent to 370,000 gene-pair tests.

The Hopkins team used a technology known as dSLAM (heterozygote diploid-based synthetic lethality analyzed by microarray) to look at the effects of 5,000 different double mutations on cell fitness in a single experiment. With this technology, only 5,000 tests would be required to map the 25 million pair-wise combinations, greatly speeding the work.

The dSLAM strategy is somewhat like pulling out parts of a radio at random to see what happens, Boeke said.

"With yeast, as with a radio, you might rip out part A or part B and find that the radio still works; but if you pull out both parts and the radio dies you would learn that A and B can compensate for each other’s absence. The parts we’re pulling out of yeast are genes, and we look to see what happens when both of the genes are pulled out."

The dSLAM technology takes advantage of DNA barcode that identifies which genes a yeast cell is missing. This is much like using a commercial barcode in a store to quickly identify items at the checkout counter. The scanner in this case is a microarray: a grid of thousands of spots on a piece of glass that holds a unique "sensor" strand of DNA that matches one of the barcodes. Machines then read the microarray to identify which of the sensors found matching barcodes that identified specific yeast cells with specific mutations. If two genes that compensated for each other are knocked out, the yeast cell dies and the microarray doesn’t record that cell, Boeke noted. That means the two genes interact with each other, he said.

"This strategy for finding interacting genes will open the door to an extraordinarily rich source of new data on DNA damage, repair, and human diseases," Boeke added.

Eric Vohr | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht Water world
20.11.2017 | Washington University in St. Louis

nachricht Carefully crafted light pulses control neuron activity
20.11.2017 | University of Illinois at Urbana-Champaign

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Antarctic landscape insights keep ice loss forecasts on the radar

20.11.2017 | Earth Sciences

Filling the gap: High-latitude volcanic eruptions also have global impact

20.11.2017 | Earth Sciences

Water world

20.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>