Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Fox Chase Researchers Discover New Mechanism of Gene Regulation

27.02.2014

Additional insights into how cancer cells use PARP1 enzyme to resist current therapies may also point to the next generation of cancer drugs

In the cells of humans and other organisms, only a subset of genes are active at any given time, depending largely on the stage of life and the particular duties of the cell. Cells use different molecular mechanisms to orchestrate the activation and deactivation of genes as needed. One central mechanism is an intricate DNA packaging system that either shields genes from activation or exposes them for use.

In this system, the DNA strand, with its genes, is coiled around molecules known as histones, which themselves are assembled into larger entities called nucleosomes. Together, nucleosomes and DNA form chromatin, which is the primary substance of chromosomes. This DNA-packaging system is vital for managing development and maintaining health. When it goes awry, cancer can be the result.

In a study published in Molecular Cell this month, Alexei V. Tulin, PhD, Associate Professor at Fox Chase Cancer Center, and colleagues reported that chemical modification of one type of histone—called H2Av—leads to substantial changes in nucleosome shape. As a consequence, a previously hidden portion of the nucleosome becomes exposed. This newly exposed portion interacts with and activates an enzyme called PARP1. Upon activation, PARP1 assembles long branching molecules of Poly(ADP-ribose), which appear to open the DNA packaging around the site of the PARP1 activation, exposing specific genes for activation.

... more about:
»Cancer »DNA »PARP1 »Regulation »activation »genes »histones

“Currently, the nucleosome is often portrayed as a stable, inert structure, or a tiny ball,” Tulin says. “We found that the nucleosome is actually a quite dynamic structure. When we modified one histone, we changed the whole nucleosome.”

In addition to reevaluating how histones control gene activation, the study also reports a new mechanism of PARP1 regulation. Many standard cancer treatments, including chemotherapy drugs and radiation therapy, damage the DNA of rapidly dividing cancer cells. However, the effectiveness of these treatments is limited. Research has suggested that standard therapies combined with drugs that inhibit PARP1 can kill cancer cells, but clinical trials testing PARP1 inhibitors in cancer patients have produced disappointing outcomes. “I believe that to a large extent the previous setbacks were caused by a general misconception of the role of PARP1 in living cells and the mechanisms of PARP1 regulation,” Tulin says. “Now that we know this mechanism of PARP1 regulation, we can design approaches to inhibit this protein in an effective way to better treat cancer.”

The ability of PARP1 to control cellular processes is regulated by nucleosomes—the basic unit of DNA packaging, consisting of a segment of DNA wound in sequence around eight histone protein cores, similar to a thread wrapped around a spool. Histones undergo different chemical modifications that play an important role in regulating the activity of genes. Through this mechanism, histones control the ability of PARP1 to activate genes and repair DNA damage.

“This mechanism of PARP1 regulation by histones is still very new,” Tulin says. “People believe that PARP1 is mainly activated through interactions with DNA, but we have found that the main pathway of PARP1 activation is through interactions with the nucleosome.” In the new study, Tulin and his colleagues reevaluated how PARP1 is activated by changes in the nucleosome. They found that the addition of a phosphate group to a histone—called H2Av—triggered the entire nucleosome to change shape, exposing previously hidden parts of the nucleosome that began to interact with and activate PARP1.

To follow up on these findings, Tulin and his team are now developing the next generation of PARP1 inhibitors. Designed to block the newly identified mechanism of PARP1 activation, these new inhibitors will specifically target PARP1, in contrast to the PARP1 inhibitors currently being tested in clinical trials.

“We expect that our targeted PARP1 inhibitors will be more effective at killing cancer cells while protecting important molecular pathways in normal cells,” Tulin says. “For this reason, we believe that the specific inhibitors we are designing hold great promise for cancer treatment.”

Co-investigators on the study include Colin J. Thomas, Elena Kotova, Mark Andrake, and Jared Adolf-Bryfogle of Fox Chase; Robert Glaser of the New York State Department of Health in Albany; and Catherine Regnard of Ludwig Maximilian University in Munich, Germany. This research was supported by grants from the National Institutes of Health (R01 GM077452 and R01 DK082623) to Tulin.

Fox Chase Cancer Center, part of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence four consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach.  For more information, call 1-888-FOX CHASE or (1-888-369-2427).

Diana Quattrone | EurekAlert!
Further information:
http://www.fccc.edu

Further reports about: Cancer DNA PARP1 Regulation activation genes histones

More articles from Life Sciences:

nachricht Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside

nachricht Chlamydia: How bacteria take over control
28.03.2017 | Julius-Maximilians-Universität Würzburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Researchers create artificial materials atom-by-atom

28.03.2017 | Physics and Astronomy

Researchers show p300 protein may suppress leukemia in MDS patients

28.03.2017 | Health and Medicine

Asian dust providing key nutrients for California's giant sequoias

28.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>