Study of New Covalent DNA Modifications and Their Roles in DNA Repair and Chromatin Organization

Collaborative Research Grants Program 2020-2022

In eukaryotes epigenetic modifications of proteins and DNA via histone modifications and cytosine methylation, respectively, play pivotal roles in differential gene expression, cellular reprogramming and embryonic development. These DNA alterations carry essential epigenetic information which govern cellular processes and are maintained after cell division. Recently, we have uncovered a new covalent post-replicative modification of DNA catalysed by poly(ADP-ribose) (PAR) polymerases (PARP1, 2 & 3) in vitro (Talhaoui et al, Nucleic acids research 44 (19), 9279-9295, 2016; Zarkovic et al, Nucleic acids research 46 (5), 2417-2431, 2018). PARPs catalyse covalent addition of ADP-ribose units to 5’- and 3'-teminal phosphates at DNA strand breaks, producing a covalent PAR-DNA complex. Although the critical role of PARP proteins in DNA damage signalling and repair of DNA breaks is well characterized and understood, the molecular mechanisms of new PARP substrate specificities remain unclear. Here, we propose to study the substrate specificity of PARP proteins and to elucidate the role of DNA PARylation, a new covalent DNA modification, in the maintenance of genome integrity.