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 Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

nachricht The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

IHP presents the fastest silicon-based transistor in the world

05.12.2016 | Power and Electrical Engineering

InLight study: insights into chemical processes using light

05.12.2016 | Materials Sciences

High-precision magnetic field sensing

05.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>