Citation
Martin A.M. Reijns, Björn Rabe, Rachel E. Rigby, Pleasantine Mill, Katy R. Astell, Laura A. Lettice, Shelagh Boyle, Andrea Leitch, Margaret Keighren, Fiona Kilanowski, Paul S. Devenney, David Sexton, Graeme Grimes, Ian J. Holt, Robert E. Hill, Martin S. Taylor, Kirstie A. Lawson, Julia R. Dorin, and Andrew P. Jackson, Enzymatic Removal of Ribonucleotides from DNA Is Essential for Mammalian Genome Integrity and Development, Cell, doi: 10.1016/j.cell.2012.04.011 (early online publication, 10 May 2012)
You would think we would know something about a process that occurs more than a million times as a cell divides
A common enzyme appears to fix errors in DNA replication that occur roughly a million times with each cell replication. Without it, we would mostly all be dead. Yet, it has taken this long to identify the extent of the enzyme’s reparative function.
What the research team was doing had nothing to do with making this discovery
Researchers at the University of Edinburgh were trying to pin down the causes of the very rare, autosomal recessive (genetic) pediatric disease called Aicardi-Goutières syndrome.
The syndrome is one of a group of white matter brain diseases called leukodystrophies. The term refers to defects in the development of the insulating myelin sheath that surrounds nerves.
The research team already knew that Aicardi-Goutières was caused by mutations (defects) in what are called RNase H2 genes.
But they wanted to see how these defects caused the disease. In pursuing their inquiry, they implemented a common genetic technique that experimentally “knocks ” the gene being studied “out” of the genetic code of the animal (or plant) under review in the lab. These altered critters are then called “knockouts.”
Knockouts are valuable for pinning down exactly what a gene (and its products) do. Presumably the animal that lacks the gene will demonstrate a loss of function — or a corresponding development of something abnormal — as compared with normal organisms.
So here, the Edinburgh team removed the RNase H2 genes in mice. That way they could see the full effect of what happens, when the genes are not only mutated, but completely gone.
Findings
The shocker:
They found that without the enzyme, the developing mouse embryos accumulated more than 1,000,000 single embedded bits of RNA in the genome of every cell, resulting in instability of their DNA.
© 2012 Medical Research Council – Institute of Genetics and Molecular Medicine, Enzyme corrects more than one million faults in DNA replication, University of Edinburgh (via Phys.org) (10 May 2012)
Why this matters
Obviously, DNA genetic coding will not work very well, when other substances (like chemically similar RNA) get incorporated into it. That is analogous to having stray letters wander into the words on a page. The resulting gobbledygook is going to be difficult to read.
With DNA, if something important cannot be read properly, either a gene product is not made at all or it gets erroneously made. In both cases, something will not work the way it is supposed to.
What is surprising in the Edinburgh finding is how common these DNA-RNA errors are and how ignorant we were that they were taking place.
Lead author, Dr. Andrew Jackson said:
“The most amazing thing is that by working to understand a rare genetic disease, we’ve uncovered the most common fault in DNA replication by far, which we didn’t even start out looking for!
More surprising still is that a single enzyme is so crucial to repairing over a million faults in the DNA of each cell, to protect the integrity of our entire genetic code.
“We expect our findings to have broad implications in the fields of autoimmunity and cancer in the future, but first we need to find out more about what effect the incorporation of RNA nucleotides is actually having on the genome.”
© 2012 Medical Research Council – Institute of Genetics and Molecular Medicine, Enzyme corrects more than one million faults in DNA replication, University of Edinburgh (via Phys.org) (10 May 2012) (paragraph split)
The moral? — In science, it is often impossible to predict what research is going to find — and that has implications for the budgeting process
At some level, the monetarily tight-fisted need to grudgingly accept that scientific progress requires the funding of “pure” research and even (sometimes) apparently useless projects.
For example, if Wikipedia is correct that only 50 cases of Aicardi-Goutières syndrome have been identified, budget-conscious institutions could certainly have argued that researching the syndrome should have been a very low (read “unfundable”) priority.
On the other hand, advocates could argue back that diseases with simple genetic correlations are exactly the ones that are most cost effective to pursue. Their relative simplicity means that they are easier and, therefore, cheaper to untangle. And the solution might have subsequently wider implications.
However, if the Edinburgh findings are accurate, it is unlikely that anyone would have predicted the breadth of applicability of this team’s result.
That is one of the joys of the scientific process.
Tagged: Aicardi-Goutières syndrome, Andrea Leitch, Andrew P. Jackson, Björn Rabe, David Sexton, DNA, enzymatic removal, enzyme, Fiona Kilanowski, gene, genetic, genome integrity, Graeme Grimes, Ian J. Holt, Julia R. Dorin, Katy R. Astell, Kirstie A. Lawson, knockouts, Laura A. Lettice, mammalian, Margaret Keighren, Martin A.M. Reijns, Martin S. Taylor, mutation, Paul S. Devenney, Pleasantine Mill, Rachel E. Rigby, ribonucleotides, RNA, RNasew H2, Robert E. Hill, Shelagh Boyle