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Keeping gene expression in check: eliciting the role of transcription in the maintenance of genome integrity

Final Report Summary - TRANSARREST (Keeping gene expression in check: eliciting the role of transcription in the maintenance of genome integrity.)

It is well documented that aberrations in DNA Damage Response (DDR) pathways are implicated in health-impairing disorders. Faulty or no repair of DNA damages may lead to irreversible mutations contributing to developmental defects and aging, whereas the progressive accumulation of mutations may lead to cancer. In this project, we aimed to understand the underlying cause of human disorders such as the Cockayne syndrome (CS), linked to defects in the mechanisms that safeguard and decode our genomic information. We identified an unanticipated mechanism for the avoidance of genomic instability in human cells that impacts on the mutagenic landscapes of genotoxin-exposed tissues, such as skin and lung, and could lower oncogenesis. This DDR mechanism is characterized by fast and widespread release of transcription elongation waves in the whole transcribed genome promoting fast and unbiased removal of damaged DNA. Our data further uncouple a dynamic synergy between chromatin and transcription dynamics that preserves gene expression accuracy and genome integrity. We also provide clear molecular explanations resolving the paradox prevailing views on rapid transcription initiation and elongation inhibition in response to DNA damage and the accelerated repair coupled to ongoing transcription. In addition to these, we developed a novel method for studying the DDR-specific ‘interactome’ that is triggered by UV-C irradiation or treatment with bulky chemotherapeutic agents. Moreover, we present the details of how transcription mis-regulation might elicit genomic instability and reveal a new avenue for drugging DNA repair, since perturbation of productive elongation in tumor cells could augment chemo-therapeutics efficacy. In conclusion, our studies have improved our understanding of how active transcription maintains healthy genomes and how, if impaired, it may contribute to health-impairing disorders.