Uncovering the network that controls double strand break repair pathway choice

Abstract

Double strand breaks (DSBs) repair is essential for normal development. While the complete inability to repair DSBs leads to embryonic lethality and cell death, mutations that hamper this repair cause genetically inherited syndromes, with or without cancer predisposition. The phenotypes associated with these syndromes are extremely varied, and can include growth and mental retardation, ataxia, skeletal abnormalities, immunodeficiency, premature aging, etc. DSBs are repaired by two major mechanisms that compete for the same substrate. Both ends of the DSB can be simple re-joined with little or no processing, a mechanism known as non-homologous end-joining. On the other hand, DSBs can be processed and engaged in a more complex repair pathway called homologous recombination. This pathway uses the information present in a homologue sequence. The balance between these two pathways is exquisitely controlled and its alteration leads to the appearance of chromosomal abnormalities and contribute to the diseases aforementioned. However, and despite its importance, the network controlling the choice between both is poorly understood. Here, we present a novel system specifically designed to unravel how the choice between both DSBs repair pathways is made, and its relevance for cellular and organismal survival, disease and development.