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DNA repair: the importance of proximity

Researchers at IRCM have shown that certain mechanisms involved in DNA repair are influenced by the intramolecular and intranuclear spatial organization of the macromolecule.

Published on 11 April 2018

Our DNA is constantly exposed to endogenous and exogenous stress factors such as UV light, genotoxic components and ionizing radiation. These stress factors can cause double strand breaks that, if unrepaired, will lead to the death of the cell. A faulty reparation of these breaks can engender gene mutations or rearrangements that may predispose the cell to malignancy. Within the cell nucleus, the chromosomes not only hold non-random positions, they also associate with specific proteins to form a more or less compact structure called chromatin. These two spatial organizational aspects have recently been shown to affect mechanisms of DNA repair, although how they do so remains a mystery. 

However, a team from IRCM recently lifted a corner of that veil when they determined how the spatial organization of chromosomes contributes to a specific type of repair called homologous recombination. This latter uses a similar sequence from elsewhere in the genome to repair the sequence at the break site. The IRCM study was conducted in yeast, a model organism in which DNA breaks can be induced in an organized manner, chromosomes repositioned, and DNA compaction modulated at the extremities of the chromosomes. 

The study showed that homologous recombination is conditioned by the distance between the two sequences, an aspect imposed by the spatial organization of the chromosomes. It also showed that tight compaction of chromatin limits the action of nucleases and prevents the loss of sequences, thus favoring repair. This is particularly important at the chromosome extremities, where chromatin compaction limits a recombinant mutagenic pathway.

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