Navigation Links
Study suggests enzyme crucial to DNA replication may provide potent anti-cancer drug target
Date:4/14/2011

LA JOLLA, CA April 14, 2011 An enzyme essential for DNA replication and repair in humans works in a way that might be exploited as anti-cancer therapy, say researchers at The Scripps Research Institute and Lawrence Berkeley National Laboratory.

The research, published in the April 15, 2011 issue of the journal Cell, focused on a member of a group of enzymes called flap endonucleases, which are essential to the life of a cell. The findings show new, clearly defined crystal structures of the enzyme FEN1 in actiondemonstrating it functions in a way opposite to accepted dogma.

"This work represents a seminal advance in the understanding of FEN1," said team leader John Tainer, professor and member of the Skaggs Institute for Chemical Biology at Scripps Research and senior scientist at Lawrence Berkeley National Lab. "The research produced very accurate structures showing DNA before and after being cut by FEN1 activity, providing a basis for understanding a whole superfamily of enzymes that must cut specific DNA structures in order for DNA to be replicated and repaired."

This superfamily includes important targets for the development of new cancer interventions, Tainer added. Many cancers show high levels of FEN1 expression, which in some cases is correlated to tumor aggression. For these cases, FEN1-specific inhibitors may have chemotherapeutic potential.

"A better understanding of FEN1 structure and function may have long-term positive benefits to human health," noted co-author Andy Arvai, a scientific associate at Scripps Research.

Working rapidly with exquisite precision

In order for DNA to replicate, it has to unwind its double helix, which is formed out of two strands of amino acids coiled together. This unwinding is done by a replication fork whereby the two strands are separated. These strands, which form two branching prongs of the replication fork, serves as a template for production of a new complementary strand.

That task is fairly straightforward on what is known as the "leading" of the two strands. The replication fork moves along from the so-called 3' (three prime) end to the 5' (five prime) end, and DNA polymerase synthesizes a 5' to 3' complementary strand.

But because the two strands are anti-parallel, meaning they are oriented in opposite directions, the work of DNA polymerase, which can only work in the 5' to 3' direction, is more difficult on the so-called lagging strand. This strand needs to be replicated in pieces, which are known as Okazaki fragments, located near the replication fork. These fragments include a "primer," a strand of RNA that serves as a starting point for DNA synthesis.

This is where FEN1 comes init removes that RNA primer on the 5' flap, which occurs every 100 base pairs or so on the lagging strand, said Tainer. It's an enormous job that has to be done rapidly and accurately in order to glue the ends of replicated DNA on the lagging strand together to eventually provide an intact chromosome. "To replicate one DNA double helix in one cell you have to cut off a 5' flap so that you don't have one base pair too many or one base pair too few, and you have to do this accurately with 50 million Okazaki primers in each cell cycle," Tainer said. "It has always been a mystery as to how FEN1 can precisely cut this flap so efficiently and so rapidly. It's an amazing, efficient molecular machine for precisely cutting DNA."

To determine what FEN1 looked like in action, Arvai led the difficult but ultimately successful effort to grow crystals of the human FEN1 protein bound to DNA. The team then used X-ray crystallography to determine the atomic structure of the complex. Using Lawrence Berkeley National Laboratory's Advanced Light Source beamline, called SIBYLS, the scientists solved three different crystal structures.

The end result was a highly detailed and accurate model showing the structures of DNA before and after being cut by FEN1.

Earlier crystal structures suggested that FEN1 first grabs onto the flap of the 5' single stranded DNA, slides down to the joint where DNA is duplicated, and cuts and patches the primer there. But the new study found that, in fact, FEN1 binds, bends, frays, and then cuts the DNA.

"It binds duplex DNA, bends it into a single-stranded DNA right at the flap, flips out two base pairs, and cuts between them," said Tainer. "This gives FEN1 very precise controla sophistication we had not expected."

Clues to cancer control

Researchers know that mutations in FEN1 can predispose humans to cancer growth because errors in flap removal can create unstable DNA that promotes cell growth and division. And studies in mice have shown that when one of two inherited FEN1 genes are knocked out, the mice are predisposed to cancer development if their DNA is damaged.

While other DNA repair systems can help compensate for FEN1 mistakes, or for missing FEN1 activity, "you need a lot of FEN1 for DNA repair and replication to work properly," Tainer said.

This suggests that, in tumors already missing one set of repair proteins, selectively inhibiting the function of FEN1 in rapidly replicating cells may prove to be an effective anti-cancer therapy. "The Achilles heel of cancer cells is defective DNA repair pathways," said Tainer, "because that makes them more sensitive to traditional therapies, such as chemotherapy and radiation. If cancer can't repair the damage these therapies do to tumors, they will die."

This is the paradox of DNA repair: while a defect in DNA repair can cause cancer, knocking out a number of backup repair systems may make tumors vulnerable to anti-cancer therapies.

"My hope is that our finding of how FEN1 works mechanistically might provide a foundation for a next-generation cancer drug," said Tainer. "We need to cut as many lifelines as possible in cancer cells in order to provide an effective treatment."


'/>"/>

Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert

Related medicine news :

1. Despite Treatment, Employees with Depression Generate Higher Absentee Costs, According to Thomson Reuters Study
2. American Council on Exercise (ACE) Study Reveals Kettlebells Provide Powerful Workout in Short Amount of Time
3. TV drama can be more persuasive than news program, study finds
4. Study carried out into biological risks of eating reptiles
5. Neuroimaging study may pave way for effective Alzheimers treatments
6. Study finds racial gaps continue in heart disease awareness
7. Luth Researchs IndicatorEDG(TM) Study Finds Americans Hopes of Achieving Their Dreams Are Fading
8. First blinded study of venous insufficiency prevalence in MS shows promising results
9. Soothing infants with food focus of childhood obesity study
10. People with anxiety disorder less able to regulate response to negative emotions, study shows
11. American Heart Association Rapid Access Journal Report: Study Finds Racial Gaps Continue in Heart Disease Awareness, Low Knowledge of Heart Attack Warning Signs Among Women
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/28/2017)... ... April 28, 2017 , ... Woolsy Corporation Limited, ... through its Nova Skin Sciences division, recently announced the launch of Allumière Antiaging ... the power of an anti-aging concentrate. , Anogeissus Leiocarpa Bark Extract ...
(Date:4/27/2017)... and DENVER (PRWEB) , ... April 27, 2017 ... ... Health, the nation’s leading respiratory hospital, based in Denver, Colorado, announced an agreement ... is enabled by the continuing support of the Jane and Leonard Korman Family ...
(Date:4/27/2017)... ... April 27, 2017 , ... Last night, Christine Collins ... the Year for her extraordinary compassion and lifelong dedication to serve others. Since ... caregivers for the prestigious award each year – identifying a CAREGiver who has ...
(Date:4/27/2017)... ... 2017 , ... Plastic Surgery Associates is excited to announce that Heather Furnas, ... upcoming Aesthetic Meeting. Held in San Diego, at the San Diego Convention Center, the ... their expertise to the Premier Global Hot Topics session, speaking on genital rejuvenation. , ...
(Date:4/26/2017)... (PRWEB) , ... April 26, 2017 , ... ... set that describes the adoption of e-prescribing as measured in Part D Medicare ... prescribers deliver prescriptions to pharmacies, either using e-prescribing, faxes or paper. The ...
Breaking Medicine News(10 mins):
(Date:4/19/2017)... Medical Corporation (TSX: CRH) (NYSE MKT: CRHM) (the "Company"), announces that it ... 2017 at the Sheraton Hotel in Toronto, Ontario ... the Company is scheduled to present on Tuesday, May 2 at ... Chairman of the Board, Tony Holler will also attend ... For more details ...
(Date:4/19/2017)... , April 19, 2017 Global ... This report on the prostate cancer therapeutics market ... global market. Increasing prevalence of prostate cancer, launch ... in the development of new drugs & therapeutic ... cancer drug due to lesser side effects are ...
(Date:4/19/2017)... , April 19, 2017  New research provides evidence ... advanced Parkinson,s, according to a study released today that will ... Annual Meeting in Boston , April ... to the treatment of Parkinson,s disease, the oral drug levodopa ... life and longevity. But as the disease progresses, the effects ...
Breaking Medicine Technology: