Damage to DNA, the vessel for genetic information, is repaired via a number of repair systems, which are nothing short of essential for protecting the genome. DNA repair occurs within the setting of chromatin, i.e., the complex of DNA and proteins more (called heterochromatin) or less (called euchromatin) coiled, or "packaged," in the cell's nucleus. How that packaging may modulate DNA repair remains unclear.

DNA double-strand breaks are one of the most dangerous types of damage as concerns genome integrity maintenance. Repairing them generally calls upon one of two mechanisms: either non-homologous end-joining (NHEJ), which accurately rejoins the broken ends; or homologous recombination (HR), which recopies a homologous sequence from a sister chromatid or a homologous chromosome. Reparation is oriented toward one or the other mechanism during the preparation of the DNA extremities resulting from the break, a process involving the MRX^MRN-Sae2^CtIP protein complex.

In a study carried out in the yeast Saccharomyces cerevisiae and published in The EMBO Journal, researchers from the Laboratory of Genome Instability and Nuclear Organization (LION) within the Genetic Stability, Stem Cells and Radiation mixed research unit at IRCM showed that the protein Sir3 orients double-strand breaks toward NHEJ. Sir3 is a heterochromatin protein already known for its role in protecting damaged chromosome ends during HR. In the study, the researchers showed that Sir3 interacted directly with the Sae2^CtIP in the MRX^MRN-Sae2^CtIP complex. More precisely, Sir3 inhibited Sae2^CtIP and prevented it from stimulating the endonuclease activity of MRX^MRN. Thus, because that endonuclease activity is indispensable for repair by the HR pathway, Sir3 favors repair by the NHEJ pathway.

This work by the LION team brings a first parcel of information on DNA double-strand break repair regulation mechanisms in yeast heterochromatin. It sheds light on the roles played by Sir3, showing that it not only participates in genome stability as a heterochromatin protein but also acts as a negative regulator for Sae2^CtIP and thus as a factor favoring the NHEJ repair pathway, which may help protect chromosomes from uncontrolled HR repair.

Future work to precisely characterize the Sir3- Sae2^CtIP binding interface could enable the conception of specific synthetic inhibitors empowering in turn a better understanding of the molecular mechanisms surely still present in humans and other mammals.