New insights into DNA repair process may spur better cancer therapies

September 30, 2013, Duke University Medical Center

By detailing a process required for repairing DNA breakage, scientists at the Duke Cancer Institute have gained a better understanding of how cells deal with the barrage of damage that can contribute to cancer and other diseases.

The insights, reported online the week of Sept. 30, 2013, in the journal Proceedings of the National Academy of Sciences, build on earlier work by the research team and identify new prospects for developing cancer therapies.

The researchers have focused on a complex series of events that cells routinely undertake to repair DNA damaged by sun exposure, smoking and even normal metabolism. If not correctly repaired, DNA breakages can result in cellular damage leading to cancer.

"We never had good assays to measure how DNA breaks are repaired, and there were few good tools to study how that repair unfolds at the molecular level," said senior author Michael Kastan, M.D., PhD, executive director of the Duke Cancer Institute. "Our work for the first time enables us to both sensitively measure the repair of DNA breaks and study the molecular mechanisms by which they occur."

DNA inside the cell faces a challenge for repairing itself because it is so compacted in the cell nucleus. Tightly wrapped in a complex of proteins called chromatin, the DNA is spooled like thread around a protein structure called a nucleosome. DNA could suffer a breakage that would go unheeded if it remained deep within the reel.

The system developed by Kastan and colleagues induced DNA breakage at defined points on the DNA strands, enabling researchers to chronicle events as the cells launched the repair process.

What they described for the first time was a choreographed interaction in which the tightly wound DNA was temporarily loosened when a key protein, called nucleolin, was recruited to the breakage site, disrupting the nucleosome spool. The process was then reversed when the nucleosome was re-formed after repair was complete.

"Our study demonstrates for the first time the functional importance of nucleosome disruption in DNA repair," Kastan said. "This nucleosome disruption allows DNA repair proteins to access the DNA lesion and begin the process of mending the breakage."

Kastan said the finding provides key insights for how cells remain healthy, as well as how the repair process could potentially be manipulated. New therapies, for instance, could target nucleolin to enhance sensitivity of tumor cells to radiation or chemotherapies, he said.

"This could give us an opportunity to make current treatments more potent," Kastan said. "That would be a next area of research, which we are especially interested in pursuing."

Explore further: Discovery about DNA repair could lead to improved cancer treatments

More information: Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair, www.pnas.org/cgi/doi/10.1073/pnas.1306160110

Related Stories

Discovery about DNA repair could lead to improved cancer treatments

September 10, 2013
Medical researchers at the University of Alberta have made a basic science discovery that advances the understanding of how DNA repairs itself. When DNA becomes too damaged it ultimately leads to cancer.

Laser pulses reveal DNA repair mechanisms

August 9, 2013
A new straightforward method enables monitoring the response of nuclear proteins to DNA damage in time and space. The approach is based on nonlinear photoperturbation.

New protein knowledge offers hope for better cancer treatment

September 19, 2013
When the pharmaceutical industry develops new medicines – for example for cancer treatment – it is important to have detailed knowledge of the body's molecular response to the medicine.

How proteins read meta DNA code

March 19, 2013
Three-quarters of the DNA in evolved organisms is wrapped around proteins, forming the basic unit of DNA packaging called nucleosomes, like a thread around a spool. The problem lies in understanding how DNA can then be read ...

Recommended for you

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.