Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Changes to DNA on-off switches affect cells' ability to repair breaks, respond to chemotherapy

04.02.2013
Double-strand breaks in DNA happen every time a cell divides and replicates.

Depending on the type of cell, that can be pretty often. Many proteins are involved in everyday DNA repair, but if they are mutated, the repair system breaks down and cancer can occur. Cells have two complicated ways to repair these breaks, which can affect the stability of the entire genome.

Roger A. Greenberg, M.D., Ph.D., associate investigator, Abramson Family Cancer Research Institute and associate professor of Cancer Biology at the Perelman School of Medicine, University of Pennsylvania, together with postdoctoral researcher Jiangbo Tang Ph.D. and colleagues, found a key determinant in the balance between two proteins, BRCA1 and 53BP1, in the DNA repair machinery. Breast and ovarian cancer are associated with a breakdown in the repair systems involving these proteins. Their findings appear in the latest online issue of Nature Structural & Molecular Biology.

The two proteins, BRCA1 and 53BP1, control which of two cell-repair mechanisms will be used: homologous recombination or non-homologous end-joining, technically speaking. This competition has proven to be a key factor in determining whether a cell becomes cancer prone as well as how a cancer cell will respond to chemotherapy.

The key step of the balance is acetylation, the chemical process of adding a compound called an acetyl group to other cellular molecules.

The researchers asked what cell signals determine whether BRCA or 53BP1 predominates at a DNA break site.

DNA in the nucleus is tightly packed around proteins called histones. Acetylation at a specific spot on histone H4 determines the answer. If H4 is acetylated at a specific location, then 53BP1 binding near the broken DNA region is strongly reduced. This leaves BRCA1 free to do the work, kicking in the homologous recombination tool to repair the break.

On the other hand, if acetylation is reduced, 53BP1 outcompetes BRCA1 at a break and the non-homologous end-joining tool repairs the break.

This mechanism can help explain resistance to a promising chemotherapy called PARP inhibition seen in patients and mouse models with BRCA1 mutations. Work from several other research teams surprisingly has shown that if neither BRCA nor 53BP1 are available, then the homologous recombination system goes into action even in the absence of BRCA1 and BRCA1 mutant cancer cells become resistant to PARP inhibitors.

Because of this, Greenberg says, there are some possible applications for making PARP chemotherapy more sensitive: "If you could inhibit specific acetylation events, then a patient's response to PARP inhibitors might be enhanced by hyperactivating 53BP1 binding to breaks in the context of BRCA1 deficient cancers. What's more, measuring the levels of acetylation at H4 might predict how responsive an individual is to PARP inhibitors."

"The story didn't fall into place the way we thought it would," says Greenberg. "We didn't realize that it was a combination of two epigenetic marks that drives the repair system. However, we were able to show that 53BP1 doesn't bind well to regions of histone H4 that are acetylated at a specific location on H4. Collaboration with Georges Mer, a structural biologist at the Mayo Clinic, helped provide the molecular basis for these findings. We think there will be further complexity to this regulation, creating the possibility for the discovery of additional mechanisms that regulate DNA repair pathways and response to therapy and potential new targets for diagnosis and therapy."

Co-authors are Nam Woo Cho, Erica M. Manion, Niraj M. Shanbhag, all from Penn, and Gaofeng Cui, Maria Victoria Botuyan, and Georges Mer, from the Department of Biochemistry and Molecular Biology, Mayo Clinic.

The research was supported by the National Cancer Institute (1R01CA138835-01, 1R01CA132878, P50CA116201), a Research Scholar Grant from the American Cancer Society, a DOD Breast Cancer Idea Award, a UPENN-FCCC SPORE Pilot Grant, and funds from the Abramson Family Cancer Research Institute and Basser Research Center for BRCA.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Another piece of Ebola virus puzzle identified
17.01.2019 | Texas Biomedical Research Institute

nachricht New scale for electronegativity rewrites the chemistry textbook
17.01.2019 | Chalmers University of Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Ultra ultrasound to transform new tech

World first experiments on sensor that may revolutionise everything from medical devices to unmanned vehicles

The new sensor - capable of detecting vibrations of living cells - may revolutionise everything from medical devices to unmanned vehicles.

Im Focus: Flying Optical Cats for Quantum Communication

Dead and alive at the same time? Researchers at the Max Planck Institute of Quantum Optics have implemented Erwin Schrödinger’s paradoxical gedanken experiment employing an entangled atom-light state.

In 1935 Erwin Schrödinger formulated a thought experiment designed to capture the paradoxical nature of quantum physics. The crucial element of this gedanken...

Im Focus: Nanocellulose for novel implants: Ears from the 3D-printer

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:

Im Focus: Elucidating the Atomic Mechanism of Superlubricity

The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.

One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...

Im Focus: Mission completed – EU partners successfully test new technologies for space robots in Morocco

Just in time for Christmas, a Mars-analogue mission in Morocco, coordinated by the Robotics Innovation Center of the German Research Center for Artificial Intelligence (DFKI) as part of the SRC project FACILITATORS, has been successfully completed. SRC, the Strategic Research Cluster on Space Robotics Technologies, is a program of the European Union to support research and development in space technologies. From mid-November to mid-December 2018, a team of more than 30 scientists from 11 countries tested technologies for future exploration of Mars and Moon in the desert of the Maghreb state.

Close to the border with Algeria, the Erfoud region in Morocco – known to tourists for its impressive sand dunes – offered ideal conditions for the four-week...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Our digital society in 2040

16.01.2019 | Event News

11th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Aachen, 3-4 April 2019

14.01.2019 | Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

 
Latest News

Brilliant glow of paint-on semiconductors comes from ornate quantum physics

17.01.2019 | Materials Sciences

Drones shown to make traffic crash site assessments safer, faster and more accurate

17.01.2019 | Information Technology

Ultra ultrasound to transform new tech

17.01.2019 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>