scientific technology

Assistant Professor of Biology Mitch McVey and his research team report that DNA polymerase theta, or PolQ, promotes an inaccurate repair process, which can ultimately cause mutations, cell death or cancer. The research is published in the July 1 edition of the open-access journal PLoS Genetics.
"Although scientists have known for several years that the PolQ protein is somehow related to the development of cancer, its exact cellular role has been difficult to pin down," says McVey."Our finding that it acts during inaccurate DNA repair could have implications for biologists who study genomic changes associated with cancer."
DNA is a double stranded molecule shaped like a spiral staircase. Its two strands are linked together by nucleotides -- guanine, cytosine, adenine and thymine -- that naturally complement one another. Under normal conditions, a guanine matches with a cytosine, and an adenine with a thymine.

How DNA Double-Strand Breaks Are Repaired

But during the course of a cell's life, the staircase can become severed into two molecules. These breaks must be repaired if the cells are to accurately replicate and pass on their genetic material. Most breaks are quickly and accurately fixed during the process of homologous recombination (HR), which uses an intact copy of DNA as a template for repair.

However, there is a second, error-prone process called end-joining repair. Here, the broken, double-stranded ends are stitched back together without regard to the original sequence. The ends of the broken strands may be altered by removal or addition of small DNA segments, which can change the genomic architecture.

In a previous paper, McVey and doctoral student Amy Marie Yu were able to demonstrate an alternative form of end-joining by studying how repair proceeds in the absence of DNA ligase 4, an important protein that links together two broken DNA ends.

After analyzing hundreds of inaccurately repaired breaks in the fruit fly Drosophila melanogaster the scientists observed two things. One, extra nucleotides were often inserted into the DNA strands at the point of the break. Second, the insertions were closely related to the original DNA sequences directly adjacent to the break.

Polymerase Theta's Role in DNA Repair and Cancer

In the current PLoS Genetics paper, McVey, Yu and undergraduate Sze Ham Chan showed that polymerase theta plays a dominant role in this alternative repair process. First, it reads the genetic material in DNA adjacent to the break and makes a copy of it. The newly copied DNA can then be used as a molecular splint that holds the broken ends together until they can be permanently joined. In addition, the scientists speculated that the PolQ protein also has the ability to unwind DNA sequences near a break, thereby facilitating alternative end-joining.
Other research groups have previously shown that levels of the PolQ protein are higher in several types of human tumors. McVey and his team are currently working to determine if a PolQ-dependent type of alternative end-joining is involved in the development of cancer in people. If this is indeed the case, the PolQ protein could represent a novel target for the development of new cancer drugs.
"Our first goal is to determine which parts of PolQ are required for its role in alternative end-joining," McVey says. "This will give us a road map for determining how its activity might be altered in a clinical setting."
This work was funded by grants from the National Science Foundation and the Ellison Medical Foundation.

Pete Beckman, Mathematics and Computer Science Division, Argonne National Laboratory
Large-scale parallel simulation and modeling have changed our world. Today, supercomputers are not just for research and development or scientific exploration; they have become an integral part of many industries. A brief look at the Top 500 list of the world’s largest supercomputers shows some of the business sectors that now rely on supercomputers: finance, entertainment and digital media, transportation, pharmaceuticals, aerospace, petroleum, and biotechnology. While supercomputing may not yet be considered commonplace, the world has embraced high-performance computation (HPC). Demand for skilled computational scientists is high, and colleges and universities are struggling to meet the need for cross-disciplinary engineers who are skilled in both computation and an applied scientific domain. It is on this stage that a new breed of high-fidelity simulations is emerging – applications that need urgent access to supercomputing resources.

For some simulations, insights gained through supercomputer computation have immediate application. Consider, for example, an HPC application that could quickly calculate the exact location and magnitude of tsunamis immediately after an undersea earthquake. Since the evacuation of local residents is both costly and potentially dangerous, promptly beginning an orderly evacuation in only those areas directly threatened could save lives. Similarly, imagine a parallel wildfire simulation that coupled weather, terrain, and fuel models and could accurately predict the path of a wildfire days in advance. Firefighters could cut firebreaks exactly where they would be most effective. For these urgent computations, late results are useless results. As the HPC community builds increasingly realistic models, applications are emerging that need on-demand computation. Looking into the future, we might imagine event-driven and data-driven HPC applications running on-demand to predict everything from where to look for a lost boater after a storm to tracking a toxic plume after an industrial or transportation accident.
Of course, as we build confidence in these emerging computations, they will move from the scientist’s workbench and into critical decision-making paths. Where will the supercomputer cycles come from? It is straightforward to imagine building a supercomputer specifically for these emerging urgent computations. Even if such a system led the Top 500 list, however, it would not be as powerful as the combined computational might of the world’s five largest computers. Aggregating the country’s largest resources to solve a critical, national-scale computational challenge could provide an order of magnitude more power than attempting to rely on a prebuilt system for on-demand computation.

Furthermore, costly public infrastructure, idle except during an emergency, is inefficient. A better approach, when practical, is to temporarily use public resources during times of crisis. For example, rather than build a nationwide set of radio towers and transmitters to disseminate emergency information, the government requires that large TV and radio stations participate in the Emergency Alert System. When public broadcasts are needed, most often in the form of localized severe weather, broadcasters are automatically interrupted, and critical information is shared with the public.

As high-fidelity computation becomes more capable in predicting the future and being used for immediate decision support, governments and local municipalities must build infrastructures that can link together the largest resources from the NSF, DOE, NASA, and the NIH and use them to run time-critical urgent computations. For embarrassingly parallel applications, we might look to the emerging market for “cloud computing.” Many of the world’s largest Internet companies have embraced a model for providing software as a service. Amazon’s elastic computing cloud (EC2), for example, can provide thousands of virtual machine images rapidly and cost effectively. For applications with relatively small network communication needs, it might be most effective for urgent, on-demand computations simply to be injected into the nation’s existing Internet infrastructure supported by Amazon, Yahoo, Google, and Microsoft.
In April 2007, an urgent computing conference at Argonne National Laboratory brought together an international group of scientists to discuss how on-demand computations for HPC might be supported and change the landscape of predictive modeling. The organizers of that workshop realized that CTWatch Quarterly would be the ideal venue for exploring this new field. This issue describes how applications, urgent-computing infrastructures, and computational resources can support this new role for computing.