Mutations in DNA have large-ranging consequences, from evolution to diseases. Dysfunctions in DNA repair and transcription, and mutagen exposures can increase the rate of mutations. It remains poorly understood how the interplay between these processes influences mutagenesis. Transcription-coupled repair (TCR) lowers mutational rates by preferentially removing lesions from the transcribed strand. Transcription has also an opposite effect by inducing transcription-associated mutagenesis (TAM). Their relative contribution on mutagenesis and the precise mechanisms remain unclear. Our hypothesis is that transcription affects mutational rate by different mechanisms that include TCR and TAM, leading to strand asymmetry of mutations due to transcription. Moreover, we recently discovered a novel function in TCR for Mediator, a conserved coactivator of transcription, and suggest its implication in mutagenesis. The aim of this interdisciplinary project is to improve our understanding of the mechanisms shaping mutational processes by deciphering how transcription and DNA repair influence mutagenesis, using an innovative approach based on microfluidics, genomics and computational analysis for mutation accumulation in budding yeast combined with mutagen exposure, as well as direct measuring of transcriptional activity. To shed light on the underlying mechanisms, we will: (i) decipher the impact of transcription and DNA repair on mutagenesis combined with mutagen treatment, using our microfluidic approach; (ii) develop a quantitative and predictive computational framework to decipher the signature of processes that induce mutations, combined with direct measurements of transcriptional activity; (iii) validate our quantitative model by performing mutation accumulation experiments and analyses based on its predictions. This project will fill important gaps in our understanding the mechanisms of mutational processes related to transcription at the origin of human diseases.

DEEP REST will investigate two remarkable deep-sea ecosystems namely polymetallic nodule fields and hydrothermal vents, including their extended peripheries. Four major areas will be investigated: the Clarion-Clipperton Zone (CCZ) and the DISCOL Experimental Area (DEA) in the Pacific Ocean for nodule fields and the northern Mid-Atlantic Ridge (nMAR), and the Arctic Mid-Ocean Ridge (AMOR) for active and inactive hydrothermal vents. These remote ecosystems are at risk of exploitation of their associated strategic metal resources, i.e. polymetallic nodules (PMN) and seafloor massive sulfides (SMS). Information on how to mitigate the impacts of future mining activities are of utmost importance. The International Seabed Authority (ISA) is currently drafting the mining code that will regulate mining operations in the Area and is working on the development of Regional Environmental Management Plans (REMPs). Moreover, at national level, the Norwegian Government recently passed the Seabed Minerals Act, and has initiated a process that may lead to commercial mining activities under Norwegian jurisdiction. The elaboration of strategies to use the oceans in a sustainable manner is fundamental as proclaimed in the “Decade of Ocean Science for Sustainable development (2021-2030)” and the “Decade on Ecosystem Restoration” launched by the UN as well as in Mission Starfish 2030 of the EU. However, questions about the impacts of mining and resilience of deep-sea communities to anthropogenic activities are still pending. DEEP REST will enhance fundamental knowledge on species and functional diversity and their interconnections to develop effective environmental management plans and regulations to protect unique and vulnerable marine habitats. We will evaluate the effectiveness of passive and innovative active restoration approaches on the recovery of ecosystem biodiversity and assess how these actions could contribute to maintaining ecosystem functions and services. A crucial and yet missing multi-dimensional analysis of alternative conservation strategies will be conducted, including an evaluation of ecosystem services under different institutional regimes. A major objective of this project is to contribute to European and international environmental policies. Therefore, we propose to integrate data from past and present studies so that scientific findings can be used to recommend concrete conservation and/or restoration actions that will also be applicable to other areas. An original outreach and awareness strategy will be developed about the governance and issues surrounding deep-sea resources including policy briefs and a theater play.