la méthylation des protéines dans les voies de réponse aux dommages à l'ADN – Methyl-DDR

Studies on protein methylation have been essentially focused on histone proteins. Thus, histones and particularly their N-terminal tails are modulated by a large number of lysine and ariginine methylation. Lysine methylation is recognized as an important indexing system demarcating transcriptionally active euchromatin and inactive heterochromatin domains in eukaryotic genome. Until now, it has been thought that, unlike other post-translational protein modifications, lysine methylation functions as more of a long-term epigenetic mechanism involved in faithfully propagating gene expression and higher-order chromatin structure through cell division and differentiation. However, the recent findings that (ii) lysine methylation is transient and can be dynamically regulated by opposing de-methylation activity and (ii) lysine methyltransferases have also non-histone substrates have suggested that lysine methylation is involved in short-term signaling mechanisms that do not necessarily involved histone methylation. In this regard, we and others have revealed that DNA-repair and checkpoint proteins are emerging as a group that is modified by protein methylation, including lysine methylation. However, the biological relevance of these methylation events remain to be unraveled. This is precisely what we propose to do in this ANR-jeune chercheur proposal by unraveling the functions of the lysine methyltransferase PR-Set7, a critical player of the DNA-damage induced signaling cascades that displays aberrant expression in cancer. By developping innovative and complementary molecular, cell biological and biochemical appoaches, we are convinced that studying PR-Set7 functions and identifying its different substrates will provide a sound basis for deciphering how lysine methylation contributes to DNA-damage response and, in fine, to understand how alterations of these methylation events contribute to tumorigenesis.