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April 2013: Massimo Pinto interviews Brad Loucas on the paper written with Michael Cornforth & entitled: the LET dependence of unrepaired chromosome damage in human cells: a break too far?

Posted By Administrator, Tuesday, September 10, 2013



Cycle Structure and its Relation to the Break Too Far Hypothesis

Figure 1. This figure illustrates a complex exchange that originated from four chromosome breaks; one each from the yellow and red chromosomes and one in each arm of the blue chromosome. This exchange was formed by one of two possible rejoining pathways. The first illustrated on the left shows the possibility where the exchange could have been formed by two separate rejoining events termed cycles. As illustrated here, one cycle accounts for the exchange between the yellow chromosome and the upper arm of the blue chromosome. Likewise, the second cycle involves the red chromosome with the lower arm of the blue chromosome. We designate this cycle structure c2 + c2 (i.e. two cycles, each forming from two breaks). The other possibility is that the exchange might have formed following the pathway on the right where all the breaks participate in the same rejoining cycle (c4). This becomes an issue with the Break Too Far hypothesis since with the c2 + c2 scenario; the "green” cycle is independent from the "white” cycle. While the breaks within a c2 cycle must be proximate; they may be sufficiently distant from the breaks of the other cycle to disallow any rejoining between them. This situation can be imagined as two simple exchanges that share a common chromosome. Under these conditions, any open breaks cannot result from a Break Too Far mechanism. With the c4 scenario, the breaks cannot interact independently from one another and Break Too Far type open breaks are a possibility. The problem is, unless we have additional information beyond that provided by mFISH it is impossible to determine which pathway was followed; c2 + c2 or c4. It is also important to note that any exchange that can be broken down into separate cycles might potentially have originated from a single rejoining cycle. Complex exchanges that can be broken down into multiple cycles are termed sequential exchange complexes (SEC).

Figure 2. In some cases, only one rejoining pathway is possible as illustrated here. This scenario is said to have a "full” cycle structure. From the drawing it can easily be seen how, on occasion breaks may be too far apart to misjoin. Here, the centromeric portion of the yellow chromosome might be too far away from the acentric portion of the green chromosome to allow them to join (reaction 4) even though all the other breaks ends involved in the exchange are proximate with their partners. This is the essence of the Break Too Far Hypothesis.

We reasoned, if the Break Too Far Hypothesis is correct, then the likelihood that an exchange would be incomplete (i.e. have an open break associated with it) would increase with the number of breaks associated with it. The fact that this type of analysis would be complicated in SECs prompted us to use non-sequential exchange complexes with full cycle structures for this determination, the results of which are plotted in fig. 3 of our paper (see the text there for further details).


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