Chemical genetics tools for investigating DNA junctions – InJUNCTION

Alternative nucleic acid structures encompass all DNA structures that deviate from the canonical Watson-Crick double helix, or duplex-DNA. These structures are currently being actively studied to understand where, when and how they fold in human cells and to identify the biological processes they are involved in. In light of the most recent results, alternative DNA structures are becoming key players in modern genetics and promising targets for chemotherapeutic interventions.

The emblematic example of alternative nucleic acid structures is undoubtedly the DNA quadruple helix, or quadruplex-DNA, whose biology is investigated for more than two decades now. In sharp contrast, the study of DNA junctions, including three-way DNA junctions, or TWJs, is only emerging. Yet, TWJs are known to be involved in severe genetic diseases referred to as REDs (for Repeat Expansion Diseases), such as Huntington diseases or Myotonic dystrophy for instance. In spite of this, no efforts have been yet invested to assess the existence and prevalence of TWJs in our genome, with the notable exception of a study that was very recently published (2021) by the consortium of the present project.

Therefore, we propose here to continue this research effort in order to decipher the biological and strategic relevance of TWJs, thanks to the implementation of the most recent and efficient chemical biology tools and techniques. This effort will be resolutely multidisciplinary (combining organic and theoretical chemistry, biochemistry and biophysics, molecular and structural biology, which are embodied by the partners of the project) and translational given that we will make all the molecular tools, protocols and techniques developed in the framework of this project available to all through a suited protection, dissemination and exploitation strategy.