Previously Unstudied Protein May Help Uncover What Triggers Some Cells to Become Cancerous

The human protein PRR14 tethers 
heterochromatin to the nuclear lamina, and reassembles in two steps at the end of mitosis, first binding to heterochromatin in anaphase, and then reattaching to the re-forming nuclear lamina in telophase. Shown are PRR14 (green), the nuclear lamina (red), and PRR14-nuclear lamina colocalization (yellow).

The human protein PRR14 tethers heterochromatin to the nuclear lamina, and reassembles in two steps at the end of mitosis, first binding to heterochromatin in anaphase, and then reattaching to the re-forming nuclear lamina in telophase. Shown are PRR14 (green), the nuclear lamina (red), and PRR14-nuclear lamina colocalization (yellow).

the topline

  • Identified more than 100 gene silencers, many previously unknown
  • One such silencer, PRR14, plays an important role in the movement of DNA within the cell nucleus
  • Disabling PRR14 causes changes in the cell nucleus that could trigger cancer

Fox Chase researchers have discovered new clues about how some genes are turned on and off inside a cell by looking closely at one previously unstudied gene, PRR14. Cell Reports published their findings online in October 2013.

The Fox Chase team investigated how a single protein can physically silence gene clusters, rendering them inactive. “This gene silencing process is a fundamental aspect of gene regulation,” says Richard Katz, PhD, lead author of the study. When the process goes awry, it can lead to cancer — for instance, when certain tumor suppressor genes are inadvertently silenced. Katz and his colleagues screened thousands of genes and found more than 100 silencers, many of them previously unknown. With PRR14, they found that the protein it encodes plays an important role in the movement of DNA within the cell nucleus.

DNA segments containing genes destined for the silent state are packaged into heterochromatin, and organized in a specific compartment at the inner periphery of the cell’s nucleus. This peripheral heterochromatin is attached to the nuclear lamina, part of the barrier separating the nucleus from the rest of the cell. Each time the cell divides, the associations between the lamina and heterochromatin dissolve and must be reestablished; any perturbations to this process can lead to changes in gene activity, which might trigger cancer.

A role in nuclear lamina structure and nuclear-cytoskeletal attachment: Normal HeLa cell, left; HeLa cell after depletion of PRR14, right. Shown are actin filaments (green), nuclear lamina (red), and DNA (blue).

A role in nuclear lamina structure and nuclear-cytoskeletal attachment: Normal HeLa cell, left; HeLa cell after depletion of PRR14, right. Shown are actin filaments (green), nuclear lamina (red), and DNA (blue).

Katz and his team found that PRR14 works as a silencer by attaching specific gene clusters, as heterochromatin, to the place in the cell nucleus set aside for silent genes. After cell division, PRR14 migrates toward the periphery of the nucleus, where it attaches the heterochromatin to the lamina. When the researchers disabled the PRR14 protein, heterochromatin began to dissociate from the lamina. Moreover, the nucleus became distorted, similar to the shape seen in cancer — suggesting that the protein also plays a key role in maintaining the structure of the nucleus.

Although PRR14 would be difficult to target as part of cancer therapy, it’s possible that treatments could disable other proteins that interact with PRR14, thereby acting on it indirectly, says Katz. “We have made significant progress in understanding how heterochromatin attaches to the nuclear lamina and how such organization is inherited as cells divide,” he adds. “An understanding of the normal function of the nuclear lamina will be critical for understanding how defects in this structure may contribute to cancer.” ■

Katz’s co-authors include Andrey Poleshko, PhD, Katelyn M. Mansfield, BS, Caroline C. Burlingame, BS, Mark D. Andrake, PhD, and Neil R. Shah, BS.
Richard Katz, PhD

Richard Katz, PhD

As part of its Cancer Center Support Grant from the National Cancer Institute, Fox Chase has launched a new Cancer Epigenetics Research Program in collaboration with scientists at Temple University Health System. The program is co-led by epigenetic research pioneer Jean-Pierre Issa, MD, director of the health system’s Fels Institute for Cancer Research and Molecular Biology, and Vasily M. Studitsky, PhD, a two-decade veteran of basic epigenetic research. Studitsky recently came to Fox Chase from Robert Wood Johnson Medical School of Rutgers, The State University of New Jersey, in New Brunswick.