Study Reveals Structure of Cell Division’s Key Molecule At the Crossroads of Chromosomes

Study Reveals Structure of Cell Division’s Key Molecule At the Crossroads of Chromosomes

  1:25:00 AM    Science Lover

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On average, one hundred billion cells in the human body divide over the course of a day. Most of the time the body gets it right but sometimes, problems in cell replication can lead to abnormalities in chromosomes resulting in many types of disorders, from cancer to Down Syndrome.

Human chromosome, with conventional nucleosomes 
containing the major form of the histones (green), and 
localization of the centromere histone H3 variant, 
CENP-A (red). (Credit: Ben E. Black, University 
of Pennsylvania School of Medicine)

Now, researchers at the University of Pennsylvania's School of Medicine have defined the structure of a key molecule that plays a central role in how DNA is duplicated and then moved correctly and equally into two daughter cells to produce two exact copies of the mother cell. Without this molecule, entire chromosomes could be lost during cell division.

Ben Black, PhD, assistant professor of Biochemistry and Biophysics, and Nikolina Sekulic, PhD, a postdoctoral fellow in the Black lab, report in the Sept. 16 issue of Nature the structure of the CENP-A molecule, which defines a part of the chromosome called the centromere. This is a constricted area to which specialized molecules called spindle fibers attach that help pull daughter cells apart during cell division.

"Our work gives us the first high-resolution view of the molecules that control genetic inheritance at cell division," says Black. "This is a big step forward in a puzzle that biologists have been chipping away at for over 150 years."

Investigators have known for the last 15 years that part of cell division is controlled by epigenetic processes, the series of actions that affect the protein spools around which DNA is tightly bound, rather than encoded in the DNA sequence itself. Those spools are built of histone proteins, and chemical changes to these spool proteins can either loosen or tighten their interaction with DNA. Epigenetics alter the readout of the genetic code, in some cases ramping a gene's expression up or down. In the case of the centromere, it marks the site where spindle fibers attach independently of the underlying DNA sequence. CENP-A has been suspected to be the key epigenetic marker protein.

However, what hasn't been known is how CENP-A epigenetically marks the centromere to direct inheritance. The Black team found the structural features that confer CENP-A the ability to mark centromere location on each chromosome. This is important because without CENP-A or the centromere mark it creates, the entire chromosome -- and all of the genes it houses -- are lost at cell division.

In this study, Black solved CENP-A's structure to determine how it specifically marks the centromere on each chromosome and surmise from that how the epigenetic mark is copied correctly in each cell division. They found that CENP-A changes the shape of the nucleosome of which it's a part, also making it more rigid than other nucleosomes without CENP-A. The nucleosome is the combination of DNA wound around a histone protein core --the DNA thread wrapped around the histone spool. The CENP-A nucleosome is copied several times to create a unique epigenetic area, different from the rest of the chromosome. CENP-A replaces histone H3 in the nucleosomes located at the centromere.

This CENP-A centromere identifier attracts other proteins, and in cell division builds a massive structure, the kinetochore, for pulling the duplicated chromosomes apart during cell division.

Besides the major advance in the understanding of the molecules driving human inheritance, this work also brings about the exciting prospect that the key epigenetic components are now in hand to engineer clinically useful artificial chromosomes that will be inherited alongside our own natural chromosomes -- and with the same high fidelity, says Black.

Co-authors are graduate student Emily A. Bassett and research specialist Danielle J. Rogers. The work was funded by National Institute for General Medical Sciences, the Burroughs Wellcome Fund, the Rita Allen Foundation, the American Cancer Society, and the American Heart Association.

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Scientists Find Direct Line from Development to Growth

Scientists Find Direct Line from Development to Growth

  9:13:00 PM    Science Lover

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It may seem intuitive that growth and development somehow go together so that plants and animals end up with the right number of cells in all the right places. But it is only now that scientists at the Duke Institute for Genome Sciences & Policy have gotten some of the first insights into how this critical coordination actually works in a plant.

Arabidopsis thaliana. (Credit: iStockphoto)

The answer is surprisingly simple.

A well-known developmental protein called Short-root has been found to directly control the activity, in both time and space, of other well-known genes involved in cell division.

"It's a remarkably straightforward answer," said Philip Benfey, director of the IGSP's Center for Systems Biology. "Considering the level of complexity that is so often found in biology, this is simplicity itself."

The researchers report their findings on July 1 in the journal Nature.

Benfey's group and others have studied the molecular-level events that determine what particular cells in Arabidopsis plants will become in considerable detail. Those events involve genetic partners Short-root and Scarecrow along with a couple of microRNAs.

Researchers also have a pretty good understanding of the intrinsic factors that allow cells to go through their cycle and divide into two daughter cells. "What was missing was a connection between the two," said Rosangela Sozzani, a postdoctoral researcher in Benfey's lab and first author of the new study.

To shed light on that connection, Sozzani and her collaborators combined a number of experimental techniques and technologies to produce a dynamic, genome-wide view of the genetic events that Short-root and its partner Scarecrow set into motion within a single type of cell. At the very same time that cells divide, Short-root and Scarecrow switch on the gene cyclin D6, they report. Cyclin D6 is one of a family of genes that govern cell growth and division.

Benfey says the discovery in plants has immediate practical relevance given the central role of plants to human life, in the form of "food, feed, fuel and fiber." It's also likely that the "logic" behind plants' growth and development will carry over to other species, perhaps even our own. In fact, he and Sozzani note, animals including humans have cyclin D6 too.

"It's not just molecules," Benfey said. "There are evolutionary relationships. Once these fundamental processes got worked out, they are likely to have been kept around."

Jim Murray from the University of Cardiff was a key collaborator on the study. The work was funded by grants from the National Institutes of Health and the National Science Foundation.

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RNA Network Seen in Live Bacterial Cells for First Time

RNA Network Seen in Live Bacterial Cells for First Time

  12:49:00 AM    Science Lover

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Scientists who study RNA have faced a formidable roadblock: trying to examine RNA's movements in a living cell when they can't see the RNA. Now, a new technology has given scientists the first look ever at RNA in a live bacteria cell -- a sight that could offer new information about how the molecule moves and works.

These are fluorescent images of E. coli bacterial cells with visualized RNA. The bar denotes 2 microns. (Credit: Image courtesy of Natalia E. Broude, Ph.D. / Department of Biomedical Engineering, Boston University)

Interest in RNA, which plays a key role in manufacturing proteins, has increased in recent years, due in large part to its potential in new drug therapies. RNA localization and movement in bacterial cell are poorly understood. The problem has been finding a way to mark RNA in a living cell so that scientists can track it, says Natasha Broude, a research associate professor at Boston University's Department of Biomedical Engineering.

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