Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How DNA Repair Helps Prevent Cancer

19.08.2013
Researchers at Michigan State University use TACC supercomputers to understand DNA bending and repair mechanisms

The biological information that makes us unique is encoded in our DNA. DNA damage is a natural biological occurrence that happens every time cells divide and multiply. External factors such as overexposure to sunlight can also damage DNA.


Results from computer simulations show that it is energetically less expensive to bend mismatch-containing, defective DNA (G:T, C:C, C:T, G:A, G:G, T:T, A:A, A+:C) vs. non-defective DNA (containing A:T or G:C base pairs). DNA repair mechanisms likely take advantage of this feature to detect defective DNA based on an increased bending propensity.

Understanding how the human body recognizes damaged DNA and initiates repair fascinates Michael Feig, professor of biochemistry and molecular biology at Michigan State University. Feig studies the proteins MutS and MSH2-MSH6, which recognize defective DNA and initiate DNA repair. Natural DNA repair occurs when proteins like MutS (the primary protein responsible for recognizing a variety of DNA mismatches) scan the DNA, identify a defect, and recruit other enzymes to carry out the actual repair.

"The key here is to understand how these defects are recognized," Feig explained. "DNA damage occurs frequently and if you couldn't repair your DNA, then you won't live for very long." This is because damaged DNA, if left unrepaired, can compromise cells and lead to diseases such as cancer.

Feig, who has used national supercomputing resources since he was a graduate student in 1998, applied large-scale computer simulations to gain a detailed understanding of the cellular recognition process. Numerical simulations provide a very detailed view down to the atomistic level of how MutS and MSH2-MSH6 scan DNA and identify which DNA needs to be repaired. Because the systems are complex, the research requires large amounts of computer resources, on the order of tens of millions of CPU core hours over many years.

"We need high-level atomic resolution simulations to get insights into the answers we are searching for and we cannot run them on ordinary desktops," Feig said. "These are expensive calculations for which we need hundreds of CPUs to work simultaneously and the Texas Advanced Computing Center (TACC) resources made that possible."

As a user of the National Science Foundation's Extreme Science and Engineering Discovery Environment (XSEDE), Feig tasked TACC's Ranger and Stampede supercomputers to accelerate his research. Ranger served the national open science community for five years and was replaced by Stampede (the sixth most powerful supercomputer in the world) in January 2013.

DNA chains are made of four precise chemical base pairs with distinct compositions. In a paper published in the Journal of Physical Chemistry B (April 26, 2013), Feig and his research team showed that the identification and initiation of repair depended on how the MutS protein bound with the base mismatches.

"We believe that DNA bending facilitates the initial recognition of the mismatched base for repair," Feig said. "Normal DNA is like a stiff piece of rubber, relatively straight. It becomes possible to bend the DNA in places where there are defects."

The biological repair machinery seems to take advantage of this propensity by ‘testing' DNA to determine whether it can be bent easily. If that is the case, the protein has found a mismatch and repair is initiated.

"When the MutS protein is deficient in certain people, they have a high propensity to develop certain types of cancer," Feig said. "We're interested in understanding, first of all, how exactly this protein works. The long-term idea is to develop strategies for compensating for this protein, basically substituting some other mechanism for recognizing defective DNA and enabling repair."

The strongest link between diseases and defects from the MutS protein has been made for a specific type of genetically inherited colon cancer.

"If an essential protein like MutS is missing or less than adequate, then the cells will not behave in a normal way," he explained. "They will turn cancerous. The cells will refuse to die and proliferate in an uncontrollable state."

In these cases, cancer is not a result of damaged DNA, but occurs because of a problem in the DNA repair mechanism itself.

"It probably has effects on many other cancers as well, because all the cancers are ultimately linked to defective DNA," he said. "If DNA damage is not recognized and repaired in time then it can lead to any type of cancer. It is a fairly generic mechanism."

According to Matt Cowperthwaite, TACC's medical informatics programs coordinator, Feig's research is enormously important for advancing our understanding of how cells repair the mistakes that inevitably occur during DNA replication. "For the first time, we have a mechanistic insight of how MutS finds mutations. This is extremely important research because the process of mutation underlies some of the deadliest diseases to affect humans, such as cancer."

Research in this area, being very fundamental in nature, throws up many challenges, but its potential in future impact, Feig believes, is tremendous.

"There are many proteins with different and important biological functions," he said. "Understanding their functions and roles in the human body will be a driving force for research in the near future."

The Texas Advanced Computing Center (TACC) at The University of Texas at Austin is one of the leading centers of computational excellence in the United States. The center's mission is to enable discoveries that advance science and society through the application of advanced computing technologies. To fulfill this mission, TACC identifies, evaluates, deploys, and supports powerful computing, visualization, and storage systems and software. TACC's staff experts help researchers and educators use these technologies effectively, and conduct research and development to make these technologies more powerful, more reliable, and easier to use. TACC staff also help encourage, educate, and train the next generation of researchers, empowering them to make discoveries that change the world.

Paromita Pain | EurekAlert!
Further information:
http://www.utexas.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>