Navigation Links
Scientists decipher missing piece of first-responder DNA repair machine
Date:10/1/2009

BERKELEY, CA Scientists from the U.S. Department of Energy's Lawrence Berkeley National Laboratory and the Scripps Research Institute have uncovered the role played by the least-understood part of a first-responder molecule that rushes in to bind and repair breaks in DNA strands, a process that helps people avoid cancer.

With this final piece of the puzzle in place, scientists can better understand how the repair mechanism fends off cancer in healthy people, and conversely, how it helps cancer cells resist chemotherapy. This could enable researchers to develop more effective therapies with fewer side effects.

The team deciphered the poorly understood component using innovative x-ray imaging techniques at Berkeley Lab's Advanced Light Source, which generates intense light for scientific research. They found that it extends from the repair machinery like a flexible arm and grabs molecules that are needed to help the machine zip severed DNA strands back together.

Their work is published in the October 2, 2009 issue of the journal Cell.

"This not only reveals how life works at a fundamental level, but also promises to guide the development of cancer treatments," says John Tainer of Berkeley Lab's Life Sciences Division and the Scripps Research Institute in La Jolla, CA. Tainer co-led the research with Paul Russell of the Scripps Research Institute.

The first-responder machine, a protein complex called Mre11-Rad50-Nbs1 (or MRN for short), homes in on the gravest kind of breaks in which both strands of a DNA double helix are cut. It then stops the cell from dividing and launches an error-free DNA repair process called homologous recombination, which replaces defective genes. If unrepaired, double strand breaks can lead to the proliferation of cancer cells.

Unfortunately, MRN's laser-like focus on DNA repair means that it also mends broken DNA in cancerous cells. This sometimes stymies chemotherapy treatments that kill cancer cells by inducing double strand DNA breaks.

Because of its key roles good and bad scientists have painstakingly studied MRN since 1995 to learn how it works in healthy people, how its mutations promote diseases such as cancer, and to possibly disable it during cancer treatment.

Despite more than a decade of effort, a critical part was missing: a protein called Nsb1 that is represented by the 'N' in MRN.

To determine Nsb1's function, the team used an Advanced Light Source beamline called SIBYLS, which yields extremely high-resolution images of the crystal structure of a protein via a technique called x-ray crystallography. The beamline is also equipped with small-angle x-ray scattering, which can determine a protein's overall architecture in solution, a critical step that approximates how a protein appears in its natural state such as inside a cell.

The scientists trained these two tools on human and yeast Nsb1 proteins. (DNA repair is so essential to life that many of the molecular machines that perform it have changed little throughout evolution). Importantly, the team studied Nbs1 bound to a partner protein that opens DNA during the first steps of double strand break repair. This enabled them to observe Nsb1 at work.

They found that Nbs1 attaches to the MR protein complex precisely where the protein complex converges on the DNA break. Nsb1 also bends in the middle like an elbow to channel molecules to the repair site.

These insights offer the best glimpse yet of how Nsb1 works and how damaged Nsb1 can lead to disease. It also suggests ways to monkey wrench MRN so that it can't repair DNA during chemotherapy. Perhaps a molecule can be wedged into Nsb1's elbow joint so it can't bend, rendering the MRN complex useless.

"These crystal and solution structures have given us an exciting leap forward in our understanding of the Nbs1 and how defects in the protein cause disease," says Scott Classen of Berkeley Lab's Physical Biosciences Division.

Adds Tainer, "Understanding how the body responds to DNA breaks is fundamental for cancer interventions and gene therapies. These results open the door to controlling the repair of DNA breaks for cancer therapeutics and gene targeting."


'/>"/>

Contact: Dan Krotz
dakrotz@lbl.gov
510-486-4019
DOE/Lawrence Berkeley National Laboratory
Source:Eurekalert  

Related medicine news :

1. University of Louisville neuroscientists hope to get people walking again
2. Oldest Skeleton in Human Family Tree Surprises Scientists
3. Scientists find obesity alone does not cause arthritis in animals
4. 2009 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
5. Scientists Discover How Chemo Can Make Women Infertile
6. Scientists May Know How Lung Cancer Spreads
7. UCSF scientists illuminate how microRNAs drive tumor progression
8. Glaxo Official Memo Urged Scientists to Withhold Information About Paxils Risks, Trial Hears; Pharmaceutical Industry Today Offers Complete News Coverage
9. University of Hawaii at Manoa CRCH scientists report adulthood body size associated with cancer risk
10. Scientists Spot Key to Breast Cancer Spread
11. Scientists Find Clue to Dangerous Side Effect of MS Drug
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Scientists decipher missing piece of first-responder DNA repair machine
(Date:3/28/2017)... Petersburg Florida (PRWEB) , ... March 28, 2017 , ... ... Marine Corp to raise money to for the Toys for Tots Literacy Campaign at ... federal budget in excess of $70 billion, the U.S. ranks at number 14 internationally ...
(Date:3/28/2017)... ... March 28, 2017 , ... AutismOne announced ... American Association of Integrative Medicine and available for application on Saturday, May 27, ... 2017 Conference in Colorado Springs. , Ed Arranga, president of AutismOne, stated: "Many ...
(Date:3/28/2017)... ... March 28, 2017 , ... The ... in Atlantic City March 13-16, was a busy spot this year. Liz Solovay ... discussed strategies for preventing outbreaks among camp communities during the upcoming 2017 camping ...
(Date:3/28/2017)... ... ... a common and unwelcomed occurrence in people of all ages, genders and ethnicities. Dermatologist Dr. ... of dealing with excess skin oil. “Oily skin is a challenge to many of my ... the oily shine while keeping the skin fresh and clean,” says Dr. Au. , What ...
(Date:3/28/2017)... ... ... thrilling adventure that reveals the mystery of Kevin’s purpose. “A Prophets Bones” is the creation ... asked of him that he had neglected to do, but this was from God and ... some who would have felt themselves to be special and better than others due to ...
Breaking Medicine News(10 mins):
(Date:3/28/2017)... BOSTON , March 28, 2017 /PRNewswire/ ... today announced a partnership with premium news ... allows pharmaceutical companies to extract key insights from ... text mining technology. The Linguamatics I2E ... top 20 global pharmaceutical companies. The Linguamatics-Dow Jones ...
(Date:3/28/2017)...  Akcea Therapeutics, a subsidiary of Ionis Pharmaceuticals, Inc. (NASDAQ: ... directors: Christopher Gabrieli , ... as chairman of the board of Akcea Therapeutics. ... Forest Laboratories. Sandford D. Smith , ... "We are excited to announce this expansion to our ...
(Date:3/28/2017)... RXi Pharmaceuticals Corporation (NASDAQ: RXII), a ... significant unmet medical needs, today announced that it ... Office (JPO) for the composition of matter of ... the treatment or prevention of fibrotic disorders, including ... retinopathy (Japanese Patent #: 6060071).  This patent includes ...
Breaking Medicine Technology: