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 Closing the carbon loop
08.12.2016 | University of Pittsburgh

nachricht Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Closing the carbon loop

08.12.2016 | Life Sciences

Applicability of dynamic facilitation theory to binary hard disk systems

08.12.2016 | Physics and Astronomy

Scientists track chemical and structural evolution of catalytic nanoparticles in 3-D

08.12.2016 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>