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By accident, scientists discover how commonest DNA replication error is corrected

15 May 2012
Appeared in BioNews 656

Scientists have discovered the enzyme in our cells which corrects the most frequently occurring mistake in DNA as cells divide.

This discovery, which may have particular implications for cancer research, was made somewhat serendipitously. The scientists, from the Medical Research Council Institute of Genetics and Molecular Medicine at the University of Edinburgh, were in fact researching Aicardi-Goutieres syndrome (AGS), a rare childhood disease.

AGS is a genetic disorder occurring from the failure of cells to correctly duplicate their DNA during cell division - a process called DNA replication. Identification of this mechanism at fault in AGS led researchers to realise its significance in healthy cells. The findings also suggest that similar faults may be at work in other diseases, such as cancer.

'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!', said Dr Andrew Jackson, who led the study.

DNA replication involves an intermediate stage where the DNA is transcribed into RNA. The researchers found that pieces of RNA are often mistakenly incorporated into the newly copied DNA.

This error was found to occur more than a million times per dividing cell. RNA is less stable than DNA and if left unfixed the RNA inserts can result in breakages in the DNA helix, as can occur in cancer cells.

In healthy cells the enzyme ribonuclease H2 (RNase H2), systematically removes aberrant RNA sequences from DNA. However, in AGS, where the gene for RNase H2 is mutated, this clean-up mechanism fails. This leads to encephalopathy (inflammation of the brain) and death in early childhood.

Studies on mice lacking the RNase H2 gene led researchers to discover its importance in maintaining genetic integrity in all cells. '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', summarised Dr Jackson.

He added: '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 […] is actually having on the genome'.

This study was published in Cell.

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