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Damaged DNA fixed in nuclear 'workshops'

Bad news for astronauts

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Researchers in the US are a step closer to understanding how the body deals with damaged DNA. The findings might pave the way for new cancer treatments, and could also be useful in predicting how likely cosmic rays are to trigger cancers in humans.

This is an active area of research for NASA because of its plans to send people to explore the red planet. The long journey to Mars would see astronauts exposed to high levels of cosmic radiation over an extended period. NASA needs to know whether or not those people it sends will be seriously damaged by the journey.

Although DNA repair work is constantly underway in the body, it is not clear exactly where the refurbishment take place: i.e. does the body fix things where the damage takes place, or do all the broken pieces get shunted to specialised DNA repair "workshops"?

Now a team at the Life Sciences Division (LSD) of the US Department of Energy, along with colleagues at NASA and the Universities Space Research Association, reports that computer models suggest that damaged DNA does indeed collect in special areas of the cell for repair.

This is a fairly controversial suggestion. Yeast is known to handle its repairs in this way, but as Professor Sylvain Costes, lead researcher on the project at the Lawrence Berkeley Laboratory, says: the genome of yeast is much smaller than ours. Many working in the field are more convinced by the idea of repairs being done "on the spot", but Costes is undaunted.

In the best tradition of interesting research, the team drew this conclusion because the predictions didn't match their data in some fairly specific ways.

Cosmic rays are highly energetic, and should leave linear, parallel tracks through any organic matter. Physics predicts that they will deposit their energy (i.e. cause damage) along the lines of a Poisson distribution, with big clumps of DNA damage being found close together, and fewer smaller areas of damage located further apart. (This is used to model the number of events occurring within a given time interval, and looks a bit like this.)

The laws of probability also suggest that more damage would occur in regions with more DNA. But in both instances, the reverse was found to be true: the damage was more likely to be found in more sparsely populated regions, and the large clumps of damage were widely distributed.

For Costes, the implications are clear: the nuclear organisation seems to confer some kind of protection to the DNA.

"DNA damage localises itself in open regions of the cell, and we saw that it also collects at the interface between DNA dense regions and these more open regions. This indicates something is going on: the nucleus is reorganising itself."

He suggests that the damaged DNA is on the move, so that it can be processed centrally for repair. This, he argues is a more efficient way of fixing damage, as it can all be done in one place.

However, the implications for astronauts are not so good. Costes explains that a system like this works well for simple breaks in DNA caused by the kind of radiation we are generally exposed to on Earth, but is less useful for dealing with the complex damage to DNA that is caused by highly energetic cosmic rays.

"The radiation we are exposed to on earth causes random, sparse breaks, but cosmic rays deposit lots of energy, causing lots of damage, in clusters. Multiple breaks mean that lots end up in the same repair factory, which makes it much more likely that there will be a mis-repair. We know that chromosomal aberrations can lead to cancers, if you are unlucky, by triggering a part of the genome that is usually silent."

The could lead to a cell developing growth advantages, and multiplying out of control, or to the wrong kind of cells for a specific location being produced.

Now Costes and his team are looking for two proteins. First, they need to identify a transporter protein that could move the damaged DNA to the repair centre. Next, and more controversially, they are on the look out for a protein could act as a temporary fix for a break in the double helix, so that a damaged part of DNA could be transferred to the repair factory without tangling up.

"The repair sequence is very complex," Costes told us. "It involves many players. The sequence is still being worked out."

The work is to be published in the August 2007 edition of PLoS Computational Biology. ®

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