Breast cancer clue: X-ray structure

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  • Published: Nov 1, 2014
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Breast cancer clue: X-ray structure

Function and form

New insights into the function of an enzyme related to the BRCA1 breast cancer protein have been revealed by US researchers in the first detailed working X-ray structure of a functionally engaged enzyme in the Polycomb Repressive Complex 1 (PRC1), a group that regulates cell development and is associated with many types of cancer. Credit: Nature/Tan et al

New insights into the function of an enzyme related to the BRCA1 breast cancer protein have been revealed by US researchers in the first detailed working X-ray structure of a functionally engaged enzyme in the Polycomb Repressive Complex 1 (PRC1), a group that regulates cell development and is associated with many types of cancer.

Robert McGinty, Ryan Henrici and Song Tan of The Pennsylvania State University, in Pennsylvania, USA, explain that the Polycombgroup (PcG) proteins are agents that bind to chromatin and block, or repress, the transcription of, and thus expression of, genes close to that location on the genome. Their presence is known to correlate with many different types of human cancer and they are, the team says, "key epigenetic regulators of stem-cell self-renewal and lineage development." For example, the enzyme PRC1 turns on or turn off the activity of genes in a cell by manipulating individual chromosome units called nucleosomes. "The nucleosome is a key target of the enzymes that conduct genetic processes critical for life," explains study leader Tan.

In the culmination of twelve years work, Tan and his colleagues have now obtained the first X-ray crystal structure of a gene regulation enzyme while it is actively working on a nucleosome. The crystal structure reveals details about how this enzyme attaches to its nucleosome target and how it thus exerts control of the gene activity that can give rise to cancerous cell replication in a particular tissue, such as that of the breast. The study also represents the first research to obtain crystal structural details of a multi-subunit protein complex bound to a nucleosome, which itself is a complex assembly of DNA and four histone proteins that package up DNA into chromatins. PRC1 ubiquitylates nucleosomal histone H2A Lys 119 using the enzyme's E3 ubiquitin ligase subunits, Ring1B and Bmi1, together with an E2 ubiquitin-conjugating enzyme, UbcH5c.

Tumour suppression

Previously, the team had obtained a crystal structure of another nucleosome-bound protein, RCC1. "This is the second important structure from the Tan lab to date of a nucleosome in complex with a protein known to interact with and modify chromatin behavior, which in turn can influence human gene expression," says Peter Preusch of the National Institutes of Health's National Institute of General Medical Sciences, which provided some funding for the research. "Along with Dr Tan's previous work detailing a nucleosome bound to the key regulatory protein, RCC1, this new structure adds to our knowledge of how proteins can regulate the structure and function of our genetic material," he adds.

Post-doctoral researcher McGinty worked with undergraduate Henrici to grow suitable crystals of the PRC1 enzyme bound to the nucleosome and undertook the X-ray crystallography. "We are excited about this crystal structure because it provides new paradigms for understanding how chromatin enzymes function," explains McGinty. The greatest intrigue lies in the fact that the work offers unexpected new insights into the workings of the BRCA1 breast-cancer-associated tumour-suppressor protein. Like PRC1, BRCA1 is a chromatin enzyme that works in a similar manner on the nucleosome. The new structure suggests that BRCA1 and PRC1 employ a similar mechanism to anchor to the nucleosome and Tan and his team are currently working towards visualizing exactly how BRCA1 itself, and other disease-related chromatin enzymes, interact with the nucleosome.

Substrate recognition

"The structure shows how a chromatin enzyme achieves substrate specificity by interacting with several nucleosome surfaces spatially distinct from the site of catalysis," the team writes. "Our structure further reveals an unexpected role for the ubiquitin E2 enzyme in substrate recognition, and provides insight into how the related histone H2A E3 ligase, BRCA1, interacts with and ubiquitylates the nucleosome."

We would like to understand how our cells operate on our DNA genetic information packaged as chromatin," Tan told SpectroscopyNow. "Our current goal is to understand how other chromatin enzymes recognize their nucleosome substrate. The PRC1/nucleosome complex is the only high resolution structure of a chromatin enzyme in complex with the nucleosome, and there are hundreds of other chromatin enzymes for which we possess little or no information on how they bind to the nucleosome." Tan adds that he hopes that the structural information they obtain will help them and others understand how these disease-related proteins function in normal and diseased cells. "We anticipate that such structural information will help in the design of new therapeutic drugs," he adds.

Related Links

Nature, 2014, 514, 591-596: "Crystal structure of the PRC1ubiquitylation module bound to the nucleosome"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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