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A new paradigm for how genes are read – ‘the elongation-first hypothesis’

4 February 2011

All living things, with their myriad variations, use an almost identical microscopic machine to read their genes. This machine - RNA polymerase - is responsible for a process called transcription, which by producing RNA from DNA, takes the first step in reading the blueprint of life that is encoded in all of our genes. Recent work funded by the Biotechnology and Biological Sciences Research Council (BBSRC) indicates that this machine may have worked in a different way in prehistoric species than was previously thought. The research is published in the February 2011 issue of Nature Reviews Mircobiology.

Structure of RNA polymerase, a formidable molecular motor and the primary driver of gene expression - a molecule that is considered by many one of the most important enzymes in biology

Structure of RNA polymerase, a formidable molecular motor and the primary driver of gene expression - a molecule that is considered by many one of the most important enzymes in biology

By studying and comparing proteins from a range of living species in intricate detail, researchers at University College London led by Dr Finn Werner, have deduced that in early organisms most of the important control of RNA polymerase took place not as it first bound to DNA, but rather as it moved along the DNA strand in a process known as elongation. This new hypothesis represents a total shift from the received wisdom about how this process took place.

Dr Werner explains: "Instinctively you might assume that RNA polymerase would be given most of its instructions about what genes to transcribe and how many times each should be read as it lands on and is recruited to the DNA. In fact, our recent discoveries suggest that in these early species, RNA polymerase was mostly controlled as it moved along the DNA during elongation and that its start point was almost irrelevant."

The researchers came to this new conclusion after detailed studies of the proteins or 'factors' that control RNA polymerase. They found that the elongation factors which guide RNA polymerase as it moves along the DNA are very similar in all types of organisms, be they microbes that live on the walls of volcanic vents at extremes of temperature and pressure 3km beneath the surface of the ocean, or complex multicellular animals like humans. By comparison, the factors that give RNA polymerase instructions at the start of its journey are fundamentally different on different branches of the tree of life, which suggest that they have emerged at a much later stage of evolution.

Dr Werner continues: "Because the elongation factors were so similar in all living organisms, we were able to deduce two things: firstly that they must be absolutely vital to life and can't be tampered with even slightly and secondly that they were probably present in the ancestors of all modern life forms.

"All species on the planet probably inherited these factors from a universal ancestor which could have inhabited deep sea vents around 3.5 billion years ago. We think that this organism would have been much less complicated than anything around today with less than two hundred genes. In an organism with such a small genome it would have mattered less where RNA polymerases started from and they probably read the DNA from any number of different points receiving instructions about what to do as they went along. You could almost argue our theory from first principles, an engine needs to be able to run before you can devise sophisticated ways to start it with an ignition key"

This new theory, coined the 'Elongation-first hypothesis' adds to our growing understanding of how organisms execute their genetic programmes in order to produce RNA and proteins from their DNA, the process fundamental to all life on earth.

Notes

For more information about this research see www.ucl.ac.uk/smb/werner

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