Around the home, regularly used tools are generally kept close at hand: a can opener in a kitchen drawer, a broom in the hall closet. Less frequently used tools are more likely to be stored in less accessible locations, out of immediate reach, perhaps in the basement or garage. And hazardous tools might even be kept under lock and key.
Similarly, the human genome has developed a set of sophisticated mechanisms for keeping selected genes readily available for use while other genes are kept securely stored away for long periods of time, sometimes forever. Candidate genes for such long-term storage include those required only for early development and proliferation, potentially dangerous genes that could well trigger cancers and other disorders should they be reactivated later in life. Cancer researchers and others have been eager to learn more about the molecules that direct this all-important system for managing the genome.
Now, researchers at The Wistar Institute and Fox Chase Cancer Center have successfully determined the three-dimensional structure of a key two-molecule complex involved in long-term gene storage, primarily in cells that have ceased proliferating, or growing. The study also sheds light on a related two-molecule complex that incorporates one member of the molecular pair, but with a different partner. This second complex is involved in storing genes in a more accessible way in cells that continue to grow. A report on the team's findings, published online on September 17, will appear in the October issue of Nature Structural and Molecular Biology.
"The two-molecule complex we studied is pivotal for protecting certain genes from expression, genes that could cause problems if they were activated," says Ronen Marmorstein, Ph.D., a professor in the Gene Expression and Regulation Program at Wistar and one of the two senior authors on the study. "This is the first time we've been able to see the structure of these molecules communicating and interacting with each other, and it provides important insights into their function."
"By defining some of the rules that dictate how these complexes are formed and operate, we have revealed a part of the difference between growing and non-growing cells," says Peter D. Adams, Ph.D., an associate member in the Basic Science Division at Fox Chase and the other senior author on the study. "This difference is crucial to the distinction between normal and cancerous cells and may inform our ability to treat this disease."
The molecular complex studied by the scientists governs the assembly of an especially condensed form of chromatin, the substructure of chromosomes. The complex is called a histone chaperone complex, responsible for inserting the appropriate histones into the correct locations within the chromatin. Histones are relatively small proteins around which DNA is coiled to create structures called nucleosomes. Compact strings of nucleosomes, then, form into chromatin.
"There are more and less condensed forms of chromatin," explains Marmorstein. "The less condensed forms correlate with more gene expression, and the more condensed forms involve DNA that's buried away and is not transcribed."
"Appropriate packaging of the DNA in the cell nucleus is crucial for proper functioning of the cell and suppression of disease states, such as cancer," says Adams.
An unanticipated observation from the study centers on the region of association between the two molecules in the complex. The researchers knew that one of the two molecules in the complex, called ASF1, associated with a particular molecular partner, HIRA, when directing assembly of the more condensed form of chromatin. But it could also associate with a different partner, called CAF1, to shepherd assembly of the less condensed form of chromatin.
On closer study, the scientists discovered that HIRA and CAF1 have nearly identical structural motifs in the regions of interaction with ASF1. This means that ASF1 can bind to one or the other molecular partner, but not to both. In other words, the interaction is mutually exclusive: A kind of decision is made by ASF1 as to whether to guide the assembly process towards the more or less condensed forms of chromatin. What determines the choice? The relevant factors are unknown for now.
Franklin Hoke | EurekAlert!
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
19.07.2018 | Earth Sciences
19.07.2018 | Power and Electrical Engineering
19.07.2018 | Materials Sciences