Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New DNA repair enzyme makes mistakes to save lives of cells

21.10.2004


Its two-step handiwork described in The EMBO Journal as most efficient of any enzyme



A newly discovered enzyme described by University of Pittsburgh researchers in a study published online today, is believed to play a key role in maintaining the integrity of a cell’s genetic information – the basis by which the life of a cell or species is preserved – by allowing its DNA to be replicated despite discovery of a mishap on the sequence that it corrects with a new mistake. Its sophisticated yet quick-fix tactics, employed at a most critical time, when typically damage can halt replication altogether, may save the cell from near certain death. Harnessing its unique capabilities could have implications for treating some cancers.

In the paper posted on the Web site of The EMBO Journal, an official journal of the European Molecular Biology Organization, the researchers describe how DNA polymerase Q, or POL-Q, has the exceptional ability to bypass damaged spots in the DNA sequence that are caused by a cell’s normal wear and tear or other abuses. In addition, it is the only known enzyme that orchestrates not only one, but two steps involved in bypassing common types of DNA damage.


POL-Q is one of 15 different DNA polymerases in human cells. These specialized enzymes carry out the duplication, proofreading and repair of DNA. DNA is a double-stranded molecule that contains genes necessary for the production of proteins, which in turn determine all aspects of a cell’s structure, function and movement. Each strand consists of nucleotides with any combination of four nitrogen-containing bases – A, T, C and G, for short – that when in proper sequence are paired with those on the opposing, complementary strand. About 1,000 nucleotides are copied per second, and mistakes in the process are rare. Problems in the sequence sometimes arise, such as a wrong or missing base or one that is damaged. If a problem somehow evades detection, it can prevent DNA from being replicated or result in a mutation in the copied DNA.

The researchers found POL-Q’s role is to detect late-stage mishaps in the replication process, specifically those that are found at a juncture called the replication fork, just before separation of the copied parent and daughter strand takes place. Rather than stop the process altogether, which would result in the cell not surviving, POL-Q comes to the rescue by performing its two-step handiwork. First, it replaces the site of a missing or chemically changed base by inserting a new base – even if its choice from one of the four bases is not complementary to the base opposite. In a correct sequence strand, A always pairs with T and G always pairs with C, but POL-Q, the researchers report, seems to favor adding an A regardless of the missing base.

Remarkably, unlike other enzymes, POL-Q engages in a second step. Perhaps as a precaution against its own "mistake" delaying or stopping replication, POL-Q adds a second base next to the first one it inserted, thereby extending the chain as if all is normal. "POL-Q’s two-step actions of insertion and extension, essentially the work that would be performed by two enzymes, are the most efficient of any known DNA polymerase. While a mispaired base may in turn result in a mutation after replication, it seems to be a small price to pay for the cell’s survival," explained Richard D. Wood, Ph.D., professor of pharmacology and the Richard Cyert Chair of Molecular Oncology at the University of Pittsburgh School of Medicine and leader of the Molecular and Cellular Oncology Program at the University of Pittsburgh Cancer Institute (UPCI).

"Based on what we have learned, our impression of POL-Q is that it does what is necessary when emergency measures are required. One analogy would be duct tape, which in a pinch can be used to mend a torn piece of luggage, for example. POL-Q does what must be done when it encounters a lesion at the DNA replication fork. It’s an efficient strategy in a crisis," he added. Further study will be required to determine how POL-Q’s less-than-perfect workmanship is corrected by other DNA repair mechanisms before the DNA undergoes replication again.

There are many causes of DNA damage – the sun’s ultraviolet rays, environmental toxins, radiation from X-rays or agents in chemotherapy – and the source determines which enzyme is involved and its technique for repair. For instance, normal wear and tear on a cell can cause a base to break off the DNA strand, and enzymes, including POL-Q, repair the DNA by inserting bases where they are found missing. POL-Q also repairs bases that are damaged or chemically altered due to abuse or stress placed on the cell, such as from radiation or oxidants, free radicals that are byproducts of oxygen consumption.

When Dr. Wood and his colleagues first identified POL-Q last year they reported that because of its protein structure it belonged to the A family of polymerases, which are known for filling gaps during DNA replication. Now with a better understanding of how its role is to permit replication to proceed, the authors note in the current study that POL-Q’s behavior is more consistent with the Y family of polymerases that bypass damage. Indeed, comparisons of its protein sequence to other polymerases in the A family yielded an interesting find: Unlike its cousins, POL-Q has three extra spans of code. "Most likely, these extra parts of the protein sequence give POL-Q its unique ability to bypass damage with such great efficiency, albeit by making frequent errors. With the aid of computational biology methods, we will be performing more detailed biochemical analyses and structural studies to determine if our impressions are correct," said Mineaki Seki, Ph.D., research associate in the basic research division at UPCI and the paper’s first author.

Additional studies also will provide researchers with more insight into POL-Q’s role in preserving the integrity of the genome. Research performed at the Jackson Laboratory and published in Molecular and Cellular Biology in tandem with Pitt’s study in The EMBO Journal, already suggests POL-Q’s importance. Knockout mice without the ability to express POL-Q had abnormal immature red blood cells. And when these mice were bred with mice without a second gene, ATM, which is important for regulating DNA’s response to radiation, few survived. Those that did were severely impaired, proof of an unstable genome. "We know that the ATM gene is intimately related to cancer lymphomas, so based on this group’s findings, it seems that an impairment or lack of POL-Q function may be tied to a cancer-prone pathway. This is certainly worth further investigation," commented Dr. Wood.

In addition to Drs. Wood and Seki, other authors of the The EMBO Journal paper are Lee Wei Yang, and Ivet Bahar, Ph.D., from the University of Pittsburgh’s Center for Computational Biology and Bioinformatics and department of molecular genetics and biochemistry; Anthony Schuffert, of the University of Pittsburgh Cancer Institute; and Chikahide Masutani, Ph.D., and Shigenori Iwai, Ph.D., from Osaka University, Japan.

Lisa Rossi | EurekAlert!
Further information:
http://www.upmc.edu

More articles from Life Sciences:

nachricht Molecular microscopy illuminates molecular motor motion
26.07.2017 | Penn State

nachricht New virus discovered in migratory bird in Rio Grande do Sul, Brazil
26.07.2017 | Fundação de Amparo à Pesquisa do Estado de São Paulo

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Carbon Nanotubes Turn Electrical Current into Light-emitting Quasi-particles

Strong light-matter coupling in these semiconducting tubes may hold the key to electrically pumped lasers

Light-matter quasi-particles can be generated electrically in semiconducting carbon nanotubes. Material scientists and physicists from Heidelberg University...

Im Focus: Flexible proximity sensor creates smart surfaces

Fraunhofer IPA has developed a proximity sensor made from silicone and carbon nanotubes (CNT) which detects objects and determines their position. The materials and printing process used mean that the sensor is extremely flexible, economical and can be used for large surfaces. Industry and research partners can use and further develop this innovation straight away.

At first glance, the proximity sensor appears to be nothing special: a thin, elastic layer of silicone onto which black square surfaces are printed, but these...

Im Focus: 3-D scanning with water

3-D shape acquisition using water displacement as the shape sensor for the reconstruction of complex objects

A global team of computer scientists and engineers have developed an innovative technique that more completely reconstructs challenging 3D objects. An ancient...

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

 
Latest News

CCNY physicists master unexplored electron property

26.07.2017 | Physics and Astronomy

Molecular microscopy illuminates molecular motor motion

26.07.2017 | Life Sciences

Large-Mouthed Fish Was Top Predator After Mass Extinction

26.07.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>