Featured Research

from universities, journals, and other organizations

Genetic Repair Mechanism Clears The Way For Sealing DNA Breaks

Date:
October 20, 2006
Source:
Washington University School of Medicine
Summary:
Scientists investigating an important DNA-repair enzyme now have a better picture of the final steps of a process that glues together, or ligates, the ends of DNA strands to restore the double helix.

In this illustration, DNA ligase (in color) encircles the DNA double helix.
Credit: Image courtesy of Washington University School of Medicine

Scientists investigating an important DNA-repair enzyme now have a better picture of the final steps of a process that glues together, or ligates, the ends of DNA strands to restore the double helix.

The enzyme, DNA ligase, repairs the millions of DNA breaks generated during the normal course of a cell's life, for example, linking together the abundant DNA fragments formed during replication of the genetic material in dividing cells.

"Our study shows that DNA ligase switches from an open, extended shape to a closed, circular shape as it joins DNA strands together," says the study's senior author Tom Ellenberger, D.V.M, Ph.D., the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular Biophysics at Washington University School of Medicine in St. Louis. "The ligase resembles a wristwatch that latches around the DNA ends that are being joined."

DNA is surprisingly reactive and under continuous assault from environmental toxins and reactive cellular metabolites. A means of repairing DNA damage is vital to maintaining the integrity of the genetic blueprint.

When these repair processes go awry, cells can malfunction, die or become cancerous, so researchers would like to know how "DNA mechanics" do their jobs. DNA ligases are attractive targets for the chemotherapy of cancer and other diseases.

DNA ligase works in concert with another ring-shaped protein known as a sliding clamp. Sliding clamps, such as the human PCNA protein, are master regulators of DNA repair, providing docking sites that recruit repair enzymes to the site of damage.

"When ligase stacks against PCNA and encircles the DNA, we think this interaction ejects other repair proteins from PCNA," says Ellenberger. "In this role, ligase may serve as the final arbiter of DNA repair, certifying that the DNA is in pristine condition and ready for the final step of DNA end joining."

In this study of DNA ligase, published in the Oct. 20 issue of Molecular Cell, Ellenberger's research group teamed with scientists from The Scripps Research Institute (TSRI), the University of Maryland School of Medicine and Lawrence Berkeley National Laboratory (LBNL).

To visualize the complicated and dynamic structures of DNA ligase and PCNA, both separately and in a complex, Ellenberger and his group worked closely with LBNL scientists to take advantage of the intense X-rays and advanced technologies of the SIBYLS synchrotron beamline at the Berkeley lab Advanced Light Source.

The researchers used a combination of X-ray crystallography and small angle X-ray scattering (SAXS). They conducted their studies with a model organism called Sulfolobus solfataricus that has many of the same biochemical characteristics of multicelled organisms, including humans.

"We expected that DNA ligase would latch shut when bound to the ring-shaped PCNA protein," says Ellenberger. "However, the SAXS experiment clearly shows that ligase remains in an open conformation enabling other repair proteins to bind PCNA until the DNA is engaged and ligase snaps shut."

Co-author John Tainer, Ph.D., professor at LBNL and TSRI, says the results reveal for the first time how these proteins can dynamically assemble and change their shape to join DNA ends during replication and repair.

The closed conformation of DNA ligase bound to DNA was imaged in a separate study previously reported by Ellenberger's group. Ellenberger says that the challenge for the future is to study the molecular choreography of ligase, PCNA and DNA in the same experiment, which will require new methods of analyzing the SAXS data.

"The SAXS methods offer a powerful means of visualizing large proteins and protein complexes that are difficult or impossible to crystallize," says Ellenberger. "Imaging of complex processes will require a variety of tools that address different levels of biological organization from the molecular level to whole animals."

Research on biological imaging is one aspect of the University's BioMed21 initiative, which calls for converting knowledge of genetic mechanisms into practical applications.


Story Source:

The above story is based on materials provided by Washington University School of Medicine. Note: Materials may be edited for content and length.


Cite This Page:

Washington University School of Medicine. "Genetic Repair Mechanism Clears The Way For Sealing DNA Breaks." ScienceDaily. ScienceDaily, 20 October 2006. <www.sciencedaily.com/releases/2006/10/061019192517.htm>.
Washington University School of Medicine. (2006, October 20). Genetic Repair Mechanism Clears The Way For Sealing DNA Breaks. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2006/10/061019192517.htm
Washington University School of Medicine. "Genetic Repair Mechanism Clears The Way For Sealing DNA Breaks." ScienceDaily. www.sciencedaily.com/releases/2006/10/061019192517.htm (accessed July 31, 2014).

Share This




More Health & Medicine News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Xtreme Eating: Your Daily Caloric Intake All On One Plate

Xtreme Eating: Your Daily Caloric Intake All On One Plate

Newsy (July 30, 2014) The Center for Science in the Public Interest released its 2014 list of single meals with whopping calorie counts. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins