Healing helicase stitches up DNA bubbles

US scientists have found an enzyme that rewinds sections of DNA whose strands have mistakenly come apart. Jim Kadonaga and Timur Yusufzai at the University of California, San Diego say the new protein is the first of what could be a whole class of DNA and RNA rewinding enzymes, yet to be discovered.

Most of the time, double-stranded DNA that is unwound by motor proteins (helicases) rewinds itself again quickly, explains Kadonaga. But sometimes, if a single strand of DNA hangs around for long enough, it will bind to proteins and form bubbles of stable unwound DNA - which can prevent genes from being expressed.

The US researchers found that the motor protein HARP (HepA related protein) attaches to these DNA single-stranded bubbles, removes the offending binding proteins, and regenerates double-stranded DNA - using up molecules of ATP, the cell’s power source, in the process. 

The team have termed this new class of enzyme an ’annealing helicase’, after the helicases which carry out the opposite function of unwinding double-stranded DNA.

’This probably should have been found 20 years ago, it just fell through the cracks,’ Kadonaga told Chemistry World. ’There are many unwinding activities [in cells] - every time you have to process DNA you have to unwind it. It therefore makes sense that you have some DNA winding activity to balance them. Anything that manipulates DNA is very important, so to find a whole new class of enzymes that actually alters DNA structure is very special.’

Mutations in HARP are known to cause Schimke immuno-osseous dysplasia, a rare genetic disease which can lead to kidney failure, problems with bone development, a loss of T cells and early childhood death. Kadonaga says the accumulation of defective DNA bubbles is the cause of the disease’s many varied symptoms. 

Jessica Tyler, associate professor at University Colorado school of medicine, believes the work has the potential to be paradigm shifting, ’ It’s something we never realised needed to be done before and I think its going to cause people to think in a way we haven’t previously. They’ve basically discovered a brand new activity and it’s pretty rare that that happens nowadays.’

Robert Tijian, a professor of biochemistry and molecular biology at Berkeley, believes this is the first of many papers in the area. ’There’s no doubt that this will widen this field of research - nobody was looking for an annealing enzyme.’ Annealing helicases could also potentially be found for RNA-DNA and RNA-RNA hybrids, expanding the research into areas such as protein synthesis, RNA stability and gene silencing. 

The researchers now hope to determine the biological function of HARP more fully, as well as to find more of these types of enzymes. 

Manisha Lalloo

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