Fox Chase Researchers Identify Mechanism That Assists in Understanding of Nuclear Organization in Cancer

“We need to understand how heterochromatin is normally organized in order to understand what can go wrong in cancer and aging,” said Katz.
“We need to understand how heterochromatin is normally organized in order to understand what can go wrong in cancer and aging,” said Katz.

PHILADELPHIA (June 16, 2020)—In a recent study, researchers at Fox Chase Cancer Center uncovered a mechanism by which the protein PRR14 acts as a tether within the cell’s nucleus to link heterochromatin and the nuclear lamina, an important feature in understanding the changes in nuclear organization in cancer.

Richard Katz, PhD, is co-lead author on the study and is a research professor in the Cancer Epigenetics Research Program at Fox Chase. The work was a collaborative project with co-lead author Andrey Poleshko, PhD, of the Department of Cell and Developmental Biology at the Perelman School of Medicine, University of Pennsylvania.

“The DNA double helix is the genetic blueprint for health and disease. Emerging research has demonstrated that packaging and organization of DNA within the cell nucleus is critical for properly deciphering the genetic blueprint,” said Katz.

In the DNA double helix, the first process of organization is the spooling of DNA onto proteins, said Katz. Proteins do most of the heavy lifting of the cell, functioning as enzymes or helping with structural organization. The “DNA plus protein” structure is referred to as “chromatin” and is organized into either euchromatin, which provides an environment for genes to be active, or heterochromatin, which is dense and inactive.

“In cancer and aging, there are striking organizational and chemical changes in heterochromatin, which may promote dysfunction,” said Katz.

According to Katz, heterochromatin is important for keeping genes turned off under specific conditions. In a previous study, Katz and other researchers found that the protein PRR14, among the 20,000 proteins of the cell, functions to organize heterochromatin at the inner edge of the nucleus, forming a characteristic layer.

“We need to understand how heterochromatin is normally organized in order to understand what can go wrong in cancer and aging,” said Katz. “Our current publication uncovered the mechanism by which the PRR14 protein functions as a molecular ‘tether’ between the inner edge of the nucleus, denoted the nuclear lamina, and heterochromatin,” he said.

In the study, Katz, Poleshko, and other researchers at Fox Chase and Penn found that the protein PRR14 binds heterochromatin and the nuclear lamina through two modular domains. Furthermore, they identified short PRR14 protein sequences that determine binding to the nuclear lamina.

After cell division, PRR14 migrates toward the edge of the nucleus, where it attaches heterochromatin to the lamina, part of the barrier that separates the nucleus from the rest of the cell. In previous work, the researchers disabled PRR14 and found that the heterochromatin began to dissociate from the nuclear lamina. In addition, the nucleus became distorted, resembling the shape seen in cancer. This suggests that the protein plays a role in maintaining the structure of the nucleus.

“We now know more about how heterochromatin is organized and we have completed further work to understand the attachment to heterochromatin,” said Katz. “One hypothesis is that the disorganization of the cancer cell nucleus provides an unexploited vulnerability. With detailed knowledge, we can begin to devise strategies to attack this vulnerability.”

The study, “The PRR14 Heterochromatin Tether Encodes Modular Domains That Mediate and Regulate Nuclear Lamina Targeting,” was published in the Journal of Cell Science.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer 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 is also one of just 10 members of the Alliance of Dedicated Cancer Centers. 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 six 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. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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