Researchers discover new mechanism of gene regulation

February 26, 2014

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.

"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 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 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."

Explore further: Cisplatin-resistant cancer cells sensitive to experimental anticancer drugs, PARP inhibitors

Related Stories

Cisplatin-resistant cancer cells sensitive to experimental anticancer drugs, PARP inhibitors

April 3, 2013
Poly (ADP-ribose) polymerase inhibitors may be a novel treatment strategy for patients with cancer that has become resistant to the commonly used chemotherapy drug cisplatin, according to data from a preclinical study published ...

Cancer research unlocks 30-year genetic puzzle

June 12, 2012
(Medical Xpress) -- Scientists at the University of Sussex have solved a 30-year genetic puzzle that could help enhance treatment for certain types of “inherited” cancers.

Novel therapeutic targets identified for small cell lung cancer

September 6, 2012
Newly discovered molecular differences between small cell lung cancer and nonsmall cell lung cancer have revealed PARP1 and EZH2 as potential therapeutic targets for patients with small cell lung cancer, according to the ...

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...

3 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

JVK
1 / 5 (1) Feb 27, 2014
Re: 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.

"In ecological terms, because of its important role in biological systems, phosphate is a highly sought after resource. Once used, it is often a limiting nutrient in environments, and its availability may govern the rate of growth of organisms."

http://en.wikiped...hosphate

That fact links ecological variation in the availability of phosphate and other nutrients to nutrient-dependent pheromone-controlled ecological adaptations in my model, which eliminates the nonsense of mutation-driven evolution as does this news release.

Nutrient-dependent/pheromone-controlled adaptive evolution: a model
http://www.socioa...53/27989

See also:
http://www.fccc.e...d/tulin/
Captain Stumpy
5 / 5 (1) Feb 27, 2014
That fact links ecological variation in the availability of phosphate and other nutrients to nutrient-dependent pheromone-controlled ecological adaptations in my model, which eliminates the nonsense of mutation-driven evolution as does this news release

@jvk
unfortunately for you... your MODEL causes MUTATIONS per the definition of MUTATION used by the geneticists, biologists and others in the field, therefore your links only SUPPORT evolution.
According to NIH
1- your model makes mutations
2- your argument predominantly is against single mutation speciation
3- You are arguing out of linguistic ignorance, inhibiting communication because you cannot understand the lexicon which governs your field/studies
JVK
1 / 5 (1) Feb 27, 2014
My MODEL can't cause anything, you idiot. It is a model of how cause and effect occur in the context of chemical ecology.

If you have experimental evidence that attests to the fact that phosphates or other nutrients cause mutations, provide the experimental evidence of cause and effect like I've been doing in a series of published works since 1995.

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.