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 Discovery of an unexpected function of a protein linked to neurodegenerative diseases
28.04.2015 | Institute for Research in Biomedicine (IRB Barcelona)

nachricht Rubber from dandelions / Scientists identify key components in the formation of rubber
28.04.2015 | Westfälische Wilhelms-Universität Münster

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fast and Accurate 3-D Imaging Technique to Track Optically-Trapped Particles

KAIST researchers published an article on the development of a novel technique to precisely track the 3-D positions of optically-trapped particles having complicated geometry in high speed in the April 2015 issue of Optica.

Daejeon, Republic of Korea, April 23, 2015--Optical tweezers have been used as an invaluable tool for exerting micro-scale force on microscopic particles and...

Im Focus: NOAA, Tulane identify second possible specimen of 'pocket shark' ever found

Pocket sharks are among the world's rarest finds

A very small and rare species of shark is swimming its way through scientific literature. But don't worry, the chances of this inches-long vertebrate biting...

Im Focus: Drexel materials scientists putting a new spin on computing memory

Ever since computers have been small enough to be fixtures on desks and laps, their central processing has functioned something like an atomic Etch A Sketch, with electromagnetic fields pushing data bits into place to encode data.

Unfortunately, the same drawbacks and perils of the mechanical sketch board have been just as pervasive in computing: making a change often requires starting...

Im Focus: Exploding stars help to understand thunderclouds on Earth

How is lightning initiated in thunderclouds? This is difficult to answer - how do you measure electric fields inside large, dangerously charged clouds? It was discovered, more or less by coincidence, that cosmic rays provide suitable probes to measure electric fields within thunderclouds. This surprising finding is published in Physical Review Letters on April 24th. The measurements were performed with the LOFAR radio telescope located in the Netherlands.

How is lightning initiated in thunderclouds? This is difficult to answer - how do you measure electric fields inside large, dangerously charged clouds? It was...

Im Focus: On the trail of a trace gas

Max Planck researcher Buhalqem Mamtimin determines how much nitrogen oxide is released into the atmosphere from agriculturally used oases.

In order to make statements about current and future air pollution, scientists use models which simulate the Earth’s atmosphere. A lot of information such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

HHL Energy Conference on May 11/12, 2015: Students Discuss about Decentralized Energy

23.04.2015 | Event News

“Developing our cities, preserving our planet”: Nobel Laureates gather for the first time in Asia

23.04.2015 | Event News

HHL's Entrepreneurship Conference on FinTech

13.04.2015 | Event News

 
Latest News

Rapid Detection of Cracks and Corrosion using Magnetic Stray Flux

28.04.2015 | Innovative Products

Discovery of an unexpected function of a protein linked to neurodegenerative diseases

28.04.2015 | Life Sciences

Rubber from dandelions / Scientists identify key components in the formation of rubber

28.04.2015 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>