Scientists from the Kavli Institute of Nanoscience at Delft University of Technology have discovered a key element in the mechanism of DNA repair. When the DNA double helix breaks, the broken end goes searching for the similar sequence and uses that as a template for repair. Using a smart new dual-molecule technique, the Delft group has now found out how the DNA molecule is able to perform this search and recognition process in such an efficient way. This week, the researchers report their findings in Molecular Cell.
A staggering problem
First, proteins form a filamentous structure on the broken DNA end. Second, this filament examines recently copied DNA or the second DNA chromosome (remember that we have two copies of each chromosome) in search of a DNA sequence that matches that of the broken end. Note that this is a daunting task: given that, for example, our human genome contains three billion base pairs, finding your few hundred base pairs of interest, is really like finding a needle in a haystack.
'Still this search process occurs within minutes and with great efficiency. How that is achieved, has been a mystery for decades. The new experiments from our group now resolve this by revealing the key step in the process, the molecular recognition step', says scientist Iwijn de Vlaminck, who was the postdoc that did the experiments in the group of prof. Cees Dekker at Delft.
Search operation
'We found that the filament's secondary DNA-binding site interacts with a single strand of the incoming double-stranded DNA during homology sampling. Recognition is achieved upon binding of both strands of the incoming DNA to each of two DNA-binding sites in the filament.'
The data indicate that the fidelity of the search process is governed by the distance between the DNA binding sites. The Delft experiments clarify what exactly happens in the sequence comparison of the two molecules, making clear why a 'wrong' sequence leads to quick dissociation of the molecules while a 'correct' sequence makes a strong bond leading up to further repair. These are the two elements that lead to the impressive speed and high efficiency of the DNA repair process.
New instrument
Molecular Cell