Structure of key epigenetics component identified
4 September 2008
Epigenetic code is a series of chemical switches that is added onto our DNA in order to ensure that the cells in our body can form different types of tissue, for example liver and skin, despite having identical DNA genetic code.
When DNA is copied from cell to cell, it is essential that the epigenetic code is also copied accurately. If not, a liver cell may divide into another type of cell, such as a nerve or eye cell. A breakdown in this system might also mean that a gene for cell growth is accidentally switched on, for example, leading to unregulated cell growth and the development of tumours.
Research published in 2007 showed the importance of the nuclear protein UHRF1 in ensuring that the epigenetic code is accurately copied. Epigenetic switches are created by the addition of a chemical group (methyl) to DNA in a process known as methylation, facilitated by the enzyme DNMT1. The researchers believe that when this code is copied, UHRF1 ensures the accuracy of the process, the way a proofreader checks a typeset article before printing.
The key element of UHRF1 involved in this ‘proofreading’ process is known as the Set and Ring Associated (SRA) domain, but the exact mechanisms by which the SRA domain accomplishes this task were unclear. Today, in three different articles, the journal 'Nature' publishes the structure of the key element of UHRF1 that facilitates this process.
"Given the increasing focus on epigenetics as a mechanism behind cancer, elucidating the structure of UHRF1 may provide crucial insights into what goes wrong," says Professor Sirano Dhe-Paganon from the Structural Genomics Consortium laboratories at the University of Toronto, Canada.
The structural papers not only represent an advance for the epigenetics field, but also an advance for how the science was done. The concurrent publication of the three papers highlights the competitive nature of this field, but in fact these papers were made possible because the SGC, in keeping with its policy of making its data freely and immediately available, made the underlying information available in the Protein Data Bank late in 2007. The availability of this information allowed the other groups to make more rapid progress in their own work.
"By releasing the structural information into the public databases as soon as it was available, we have ensured that other research groups could make immediate and maximum benefit from the shared knowledge," says Professor Dhe-Paganon.
Professor Masahiro Shirakawa from Kyoto University, Japan, openly acknowledges that the SGC data was crucial to his team's paper, which also appears in today's edition of 'Nature'.
"We would like to express our gratitude to the researchers at the SGC for making their [findings] available on [the] net," says Professor Shirakawa. "Structural biology is a complex but very important field, with the potential to drive forward important research in many areas. The information provided by the SGC significantly speeded up our own work."
The SGC's "open source" policy contrasts with the accepted practice in the structural biology field, which is to make the underlying data available only after the work appears in print. However, Professor Al Edwards, Director of the SGC, believes strongly that data such as the 3D structure of proteins should be made freely available as soon as they are discovered.
"From the outset, it's been important to us to release our structural data immediately," says Professor Edwards. "This is contrary to the way many scientists work, but we believe it is crucial for facilitating scientific and medical progress, and our policy has not inhibited our ability to publish our work in the top journals. All the protein structures studied by the SGC have medical relevance and making them freely available ensures that scientists are able to use them to make progress in our understanding of disease and the development of new drugs."
Image: Structure of the nuclear protein UHRF1; SGC-Toronto
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Notes for editors
1. Avvakumov G V et al. Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature, 4 September 2008.
2. The Structural Genomics Consortium (SGC) is a not-for-profit organization that aims to determine the three-dimensional structures of proteins of medical relevance, and place them in the public domain without restriction. The SGC operates out of the Universities of Oxford and Toronto and Karolinska Institutet, Stockholm, and works on structures of proteins from its funder-created Target List of around 2000 proteins, which comprises human proteins associated with diseases such as cancer, diabetes, inflammation, and genetic and epigenetic diseases, as well as proteins from human parasites such as those that cause malaria. The SGC released its 450th structure in June 2007. Over the next four years, the SGC will generate and release the structures of another 600 proteins from the Target List, including several human integral membrane proteins.
3. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.
4. Established in 1827, the University of Toronto is Canada's largest and most influential university with almost 12 000 faculty and staff working at three campuses and ten academic hospitals in the Toronto region. Its world-leading scholars teach more than 60 000 students in 841 distinct undergraduate programs as well as 520 graduate and 42 professional programs. According to Thomson ISI data, U of T faculty also publish more research than any other publicly-funded university in North America. And with over 400 000 alumni in more than 130 countries around the world, U of T is truly global in reach and impact.