New DNA repair mechanism unveiled
A new interplay between TREX-2 complex (containing the GANP subunit) and
the desubiquitination module (DUB) of the SAGA co-activator complex was discovered, that is necessary to maintain monoubiquitinated (Ub) histone H2B levels on chromatin required for efficient DNA repair through homologous recombination.
July 27, 2018
DNA repair is a set of processes that identify and correct damage to DNA molecules: it is essential to maintaining the integrity of our genome. Its dysfunction can lead to the death of the affected cell, but also be responsible for diseases such as cancer. In this study, Laszlo Tora's team, in collaboration with Evi Soutoglou's team, both located at the IGBMC (CNRS/Inserm/University of Strasbourg), identified an antagonistic relationship between the TREX-2 complex and a SAGA complex module. Researchers have shown that this balance is necessary for effective repair of human DNA by homologous recombination. These results are published on July 27th 2018 in the Journal of Cell Biology.
Our genetic heritage is constantly threatened by environmental attacks that damage DNA such as ionizing radiation or chemicals. The most serious event for a cell is the appearance of a double-stranded break in one of its chromosomes. Such a break needs to be repaired. Either the repair is carried out in an optimal way and the cell resumes its normal cycle of division, or the break is not repaired correctly and it will cause the appearance of chromosomal anomalies which can lead to numerous diseases, in particular cancer.
Fortunately, the cell has several mechanisms to identify DNA damage and repair it. One of the main pathways is homologous recombination, which uses one of the chromosome strands as a model to faithfully restore genetic information at the site and near the rupture of a second strand. This repair requires remodeling of chromatin, a process in which protein machineries are depositing or removing histone modifications, the main protein components of these cellular structures. Ubiquitination and deubiquitination of histones are part of these so-called post-translational modifications.
In this study, researchers showed that, after DNA damage, a balance between ubiquitinated and de-ubiquitinated histone H2B is necessary to ensure faithful repair by homologous recombination.
The researchers discovered that this balance is maintained by the antagonistic actions of two cellular protein complexes involved in gene expression, the TREX-2 and SAGA complexes. Disturbance in the integrity of these complexes induces a disrupted balance with consequent failure in the repair process and deleterious outcomes for the cells.
This work reveals new highlights about how these two protein complexes are acting in the cell and underlines the importance of their interconnected activity on DNA repair and cell survival.
This study was supported by the European Research Council (ERC) and the ANR.