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Monday, July 2, 2012

A novel repair mechanism for DNA breaks


There are many ways in which DNA can be damaged. Our own metabolic processes generate free radicals that can wreak havoc, and so can exposure to ionizing radiation. When there’s damage to only one strand of the double helix, enzymes can successfully fill in the blanks by copying the intact strand. When both strands break, the entire piece of DNA must be reattached in the correct position. Failure to do so can result in chromosomal rearrangements that can lead to cancer. Unfortunately when an entire piece of DNA is snapped off there’s no template to tell the repair enzymes where it was supposed to go. Or is there?

Recall that, as diploid creatures, we have two homologous (containing the same genes) copies of each chromosome (see image left). Even if one of these chromosomes is severed, the other is almost certainly whole. Manoj Gandhi, Viktoria Evdokimova and their colleagues from the University of Pittsburgh have found that the intact and broken chromosomes contact each other at the site of the double stranded break, and that this contact may be involved in repairing the faulty chromosome.

The researchers discovered this phenomenon by using arm specific paints to color the different parts of each chromosome. Geneticists label the part of the chromosome on one side of the centromere the ‘p arm’ and the other part the ‘q arm’. Thus, they could actually watch the red q arms or green p arms of homologous chromosomes come into contact with each other. Such contact increased significantly after a double-stranded break.

This sort of pairing up of chromosomes is well known to occur during meiosis. At that time, the two homologous chromosomes first exchange bits of DNA with each other (recombination, or crossing-over) and then are segregated into the haploid germ cells. Unlike reproductive pairing, the contact seen here does not extend throughout the entire chromosome but is limited to the damaged region.

To see just how limited that contact was, the scientists induced double stranded breaks at specific sites, both within and outside of genes. Colored DNA probes were used to show exactly when and where the chromosomes made contact. Interestingly, contact between homologous chromosomes only occurred when the break was within a gene and only when RNA was being transcribed. Noncoding regions of chromosomes did not receive this extra repair help.

Needless to say, our two homologous chromosomes originate from our two parents. As primary investigator Yuri Nikiforov points out:
So, after all, our parents not only provide us with their genetic information, but their chromosomes keep fixing each other for as long as we live.
That’s rather a nice thought.