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Collisions of protein machines cause DNA replication derailment

23 February 2011

Scientists have published results that will forever change the way researchers view the interplay between gene expression, DNA replication and the prevention of DNA damage.

DNA damage, if not kept in check, can lead to many problems including cancers. Researchers, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust and working at The University of Nottingham, have shown that the process of replication is even riskier than originally thought. This new information is published tomorrow (24 February) in the journal Nature.

Lead researcher Panos Soultanas, a Professor of Biological Chemistry from The University of Nottingham School of Chemistry said "Consider DNA as a bi-directional rail track with two types of train: a big fast one like an eight-carriage cross country train and a small slow one like a two-carriage regional train. As it travels, the big train - the DNA replisome - is responsible for copying the DNA e.g. when a cell is preparing to divide. And the small train - the RNA polymerase - makes its journey to deal with the expression of genes contained within the DNA sequence."

Just like trains, collisions between proteins moving along a strand of DNA can be catastrophic and this is one reason why areas of DNA that are being used a lot are particularly prone to damage. Until now it was thought that only head-on collisions between the DNA replisome (the big, fast, cross country train) and the RNA polymerase (the small, slow, regional train) could lead to serious DNA damage. This research shows that collisions between big and small trains running in the same direction can be just as dangerous and hence the problem in areas of high use is exacerbated.

Professor Soultanas said "Until now we thought that if the fast and slow protein-trains meet going in the same direction along the track then the faster DNA replication train just slows down and follows along behind the slower gene expression train until it has finished its job and moved out of the way. Our new research shows that this isn't the case at all and in fact they do collide quite often causing what, in this analogy, we could only describe as a major derailment!"

When the DNA replisome falls off the DNA there are other proteins - called "restart replication proteins" - that come in to help get it back on track. Although this ensures that DNA replication can continue, it can potentially increase the risk of mistakes occurring during the copying process, particularly if such restart replication proteins are malfunctioning. In some cases these mistakes can lead to problems e.g. if the mistake causes a genetic malfunction that can lead to a cancer developing.

Describing what happens to the DNA replisome in areas of DNA where there are many RNA Polymerases working on genes that are in high use, Professor Soultanas said: "We are now realizing that when there are a lot of slow moving trains close together on the track, the fast moving train is faced with a huge obstacle and any failure to safely negotiate these areas could easily result in significant errors. Therefore, replication restart mechanisms are of vital importance to ensure accurate copying of the genetic material"

Professor Douglas Kell, Chief Executive, BBSRC said "This is exciting news and an excellent achievement. Biological sciences as a discipline is unique because there are a collection of key ideas, tools, techniques and processes that are applied across an enormous range of topics. The interplay between gene expression, DNA replication and the prevention of DNA damage is an example of just such a tenet of biology and so this result has the potential to touch on research right across BBSRC's portfolio and beyond."

ENDS

Notes to editors

This research is published in a paper entitled "Co-directional replication-transcription conflicts lead to replication restart" in the 24 February 2011 edition of Nature.

About The University of Nottingham

The University of Nottingham, described by The Sunday Times University Guide 2011 as 'the embodiment of the modern international university', has award-winning campuses in the United Kingdom, China and Malaysia. It is ranked in the UK's Top 10 and the World's Top 75 universities by the Shanghai Jiao Tong (SJTU) and the QS World University Rankings. It was named 'Europe's greenest university' in the UI GreenMetric World University Ranking, a league table of the world's most environmentally-friendly higher education institutions, which ranked Nottingham second in the world overall.

The University is committed to providing a truly international education for its 40,000 students, producing world-leading research and benefiting the communities around its campuses in the UK and Asia.

More than 90 per cent of research at The University of Nottingham is of international quality, according to the most recent Research Assessment Exercise, with almost 60 per cent of all research defined as 'world-leading' or 'internationally excellent'. Research Fortnight analysis of RAE 2008 ranked the University 7th in the UK by research power. The University's vision is to be recognised around the world for its signature contributions, especially in global food security, energy & sustainability, and health.

More news from the University at: www.nottingham.ac.uk/news

About the Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk

About BBSRC

BBSRC is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £470M in a wide range of research that makes a significant contribution to the quality of life in the UK and beyond and supports a number of important industrial stakeholders, including the agriculture, food, chemical, healthcare and pharmaceutical sectors.

BBSRC provides institute strategic research grants to the following:

  • The Babraham Institute
  • Institute for Animal Health
  • Institute of Biological, Environmental and Rural Sciences (Aberystwyth University)
  • Institute of Food Research
  • John Innes Centre
  • The Genome Analysis Centre
  • The Roslin Institute (University of Edinburgh)
  • Rothamsted Research

The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research.