Researchers Report New Findings About Nuclear Matrix

BUFFALO, N.Y. -- University at Buffalo researchers who pioneered basic research on the nuclear matrix, the internal structure of the cell nucleus, are reporting new data on its role in organizing and integrating genetic processes this week at the first major international conference devoted to the nuclear matrix.

The new data include identification of a new nuclear matrix protein and its role in genetic processes, identification of replication sites in the nucleus, and the use of advanced laser microscopy and three-dimensional computer-imaging techniques to study replication sites.

Ronald Berezney, Ph.D., professor of biological sciences at UB, and the first researcher to propose the idea of a nuclear matrix, is principal organizer of the Keystone Symposium on The Nuclear Matrix: Involvement in Replication, Transcription, Gene Splicing and Cellular Regulation. It is being held on Hilton Head Island, SC.

Proposed by Berezney and others in the 1970s, the idea that the nucleus had an intricate structure that affected replication and other genetic processes was received skeptically at first.

Since then, however, the development of advanced techniques, such as laser confocal microscopy and three-dimensional imaging, has allowed scientists to view the architecture of the nuclear matrix. Now the idea of a "structural code" inside the nucleus is gaining increasing acceptance among biologists.

According to Berezney, the work that will be presented by his group and others at the conference is part of an overall effort to understand the relationship between the architecture of the cell nucleus and genomic organization and regulation.

Those relationships may also have important implications for the understanding and treatment of certain diseases.

"While research on the human genome project is providing information on the linear order of genes on our chromosomes, the UB research on the nuclear matrix is intent on taking things one giant leap further: mapping where the linear array of genes functions in three-dimensional space," he said.

The UB group is one of the few groups studying the fundamental mechanisms behind the nuclear matrix.

Already, Berezney and colleagues at UB have used the advanced techniques to pinpoint specific replication sites along the chromosome, information that will eventually provide insight into how the replication of individual genes is organized and regulated in three-dimensional space.

"We want to understand how genes express themselves in three dimensions," he said. "When the chromosome unravels in the newly assembled cell nucleus following cell division, different regions of a chromosome or different chromosomes may actually be close in three dimensions, and those spatial relationships may be regulated."

In other words, he said, the linear array of genes along the chromosome is transformed into a three-dimensional arrangement.

One of the keys to a better understanding of the nuclear matrix and its architecture is the identification of the specific proteins that make up the nuclear matrix and how they interact.

Berezney's group, which has pioneered this field by cloning and sequencing the very first nuclear matrix protein, has now identified and will report on a new nuclear-matrix protein that may be involved in the mechanism of gene splicing or its regulation. While it does not appear to directly affect the splicing of RNA, it may affect proteins called splicing factors, by acting as a "molecular chaperone" to target certain critical proteins and/or assembling them into regions in the nucleus where splicing takes place.

The protein is also of interest because it shows significant structural similarity to cyclophilin, an important regulatory protein that may play a role in HIV (AIDS) infectivity.

The UB researchers also intend to apply their approaches to chromosome translocation, a process where a piece of one chromosome moves to another one and may prevent it from functioning normally.

Chromosome translocations are of interest in part because they occur frequently in cancers, such as those of the breast and prostate and in leukemia.

"It is very likely that an elevated level of chromosome translocations could be one basis for understanding cancer," said Berezney.

In one example, the UB researchers will be looking at translocations that occur with the genes for acute lymphoblastic leukemia (ALL) and acute myloid leukemia (AML).

"It is striking how often this chromosome aberration appears in patients with these diseases, especially children," said Berezney.

In these cases, the gene is translocated from chromosome 11 to a different chromosome, possibly signaling an abnormality.

By looking at the three-dimensional structures of the chromosomes involved inside the functioning cell nucleus, the UB researchers are trying to see if they are close in three-dimensions, which could account for their tendency to translocate. The role of replicating the DNA at these critical sites will also be investigated.

"No one knows for sure why or how chromosome translocation occurs," said Berezney. "We do know that the two chromosomes have to make physical contact, over a kind of demilitarized zone. It depends on which chromosome is the dominant force, and we are suggesting that it's controlled three-dimensionally."