In certain cancers, including prostate cancer and lymphomas, members of the Polycomb group (PcG) of proteins appear to abnormally switch genes from on to off, or "silence" them.
The latest work revealed that they do so by placing a small molecule called ubiquitin on a portion of the protein histone H2A, which is tightly associated with DNA.
"This discovery allows greater understanding of how expression of a gene can go awry and may identify a potential target for treatment in certain cancers," said the study's senior author Dr. Yi Zhang, associate professor of biochemistry and biophysics in UNC's School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center.
The new findings appear in the online issue of the journal Nature and will be published in print in October.
Within the cell nucleus, DNA is wrapped tightly around nucleosomes, globular structures composed of four abundant proteins called histones, Zhang said.
"Histone proteins, including H2A, are important in two ways. One is to package genomic material into the nucleus and the other is to regulate processes involving DNA including gene expression, or transcription."
In 1975, histone H2A was the first molecule ever described to be ubiquitinated, or modified by the attachment of the protein ubiquitin, but neither the consequence of H2A ubiquitination nor the molecules responsible were known.
Now, 29 years later, work by Zhang and colleagues has provided answers to both questions.
"Since Polycomb-group proteins have been previously linked to cancer, we anticipate that the ubiquitination of histone H2A will also be linked to some types of cancer," said Zhang.
By dividing human cellular extract into smaller and smaller fractions, the UNC scientists were able to isolate and identify the proteins involved in H2A ubiquitination.
"To our surprise, it happened to be one of the Polycomb-group proteins," said Zhang. "We've uncovered a new mechanism used by these well-characterized proteins."
The new findings have implications for epigenetics, which is the study of transcriptional control that does not involve DNA sequence and that can be inherited from one generation of cells to another. Along with ubiquitination, epigenetic modifications also include histone methylation, acetylation and DNA methylation.
"The PcG silencing system is one of the best-studied model of epigenetic regulation systems," said Zhang.
PcG proteins function in protein complexes to repress transcription of genes that are likely to include key regulators of the cell cycle.
The new study demonstrated that a gene normally silenced by the complex becomes switched on in cells when one of the PcG proteins essential for the ubiquitination of H2A has been eliminated, Zhang said.
"Although the mechanism by which H2A ubiquitination contributes to PcG silencing is still unknown, the identification of the responsible enzyme should allow us to better understand the PcG silencing system and how it relates to human disease, such as cancer," said Zhang.
Co-authors with Zhang include postdoctoral researcher Dr. Hengbin Wang from UNC's department of biochemistry and biophysics; Drs. Liangjun Wang and Richard S. Jones from Southern Methodist University; Drs. Hediye Erdjument-Bromage and Paul Tempst from Memorial Sloan-Kettering Cancer Center; and Dr. Miguel Vidal from the Center of Biological Investigations in Madrid. Funding for the study came from the National Institutes of Health.
Note: Contact Zhang at 919-966-3036 or yi_zhang@med.unc.edu.
School of Medicine contact: Leslie H. Lang, 919-843-9687 or llang@med.unc.edu
UNC Lineberger contact: Dianne G. Shaw, 919-966-7834 or dgs@med.unc.edu
Journal
Nature