Navigation Links
Scientists decipher missing piece of first-responder DNA repair machine

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
DOE/Lawrence Berkeley National Laboratory

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:
Related Image:
Scientists decipher missing piece of first-responder DNA repair machine
(Date:6/25/2016)... Oklahoma City, Oklahoma (PRWEB) , ... June 25, ... ... to helping both athletes and non-athletes recover from injury. Recently, he has implemented ... for the Oklahoma City area —Johnson is one of the first doctors to ...
(Date:6/25/2016)... ... June 25, 2016 , ... Conventional wisdom preaches the benefits of ... of the latter, setting the bar too high can result in disappointment, perhaps even ... progress toward their goal. , Research from reveals that behind ...
(Date:6/24/2016)... ... June 24, 2016 , ... Those who have experienced traumatic events ... turn to unhealthy avenues, such as drug or alcohol abuse, as a coping mechanism. ... tools for healthy coping following a traumatic event. , Trauma sufferers tend to feel ...
(Date:6/24/2016)... ... ... was in a crisis. Her son James, eight, was out of control. Prone to extreme ... “When something upset him, he couldn’t control his emotions,” remembers Marcy. “If there was ... other children and say he was going to kill them. If we were driving ...
(Date:6/24/2016)... ... June 24, 2016 , ... Global law firm Greenberg Traurig, ... Elite. The attorneys chosen by their peers for this recognition are considered among the ... Traurig Shareholders received special honors as members of this year’s Legal Elite Hall of ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... June 23, 2016 Capricor ... ), a biotechnology company focused on the discovery, ... that patient enrollment in its ongoing randomized HOPE-Duchenne ... exceeded 50% of its 24-patient target. Capricor expects ... third quarter of 2016, and to report top ...
(Date:6/23/2016)... INDIANAPOLIS , June 23, 2016 /PRNewswire/ ... Diabetes Tomorrow,s Leaders Scholarship is any indication, the future ... today online at by the Diabetes ... stand in the way of academic and community service ... scholarship program since 2012, and continues to advocate for ...
(Date:6/23/2016)... The vast majority of dialysis patients currently ... are usually 3 times a week, with treatment times ... time, equipment preparation and wait time.  This regimen can ... patients who are elderly and frail.  Many elderly dialysis ... centers for some duration of time. Residents ...
Breaking Medicine Technology: