The histone methyltransferase NSD3 contributes to sister chromatid cohesion and to cohesin loading at mitotic exit

Abstract Sister chromatid cohesion guarantees the correct transmission of chromosomes to daughter cells, and this multi-step process occurs throughout the cell cycle. Loading of the core cohesin complex onto chromatin takes place during mitotic exit, cohesion establishment happens during DNA replication, and the timely removal of cohesin occurs during mitosis. While cohesion establishment and mitotic cohesion dissolution have already been explored, the regulation of cohesin loading is not as well understood. Here, we report that the histone-lysine N-methyltransferase NSD3 is an essential factor in sister chromatid cohesion and mitotic progression, and that this occurs before and not after entry into mitosis. We establish that NSD3 interacts with the cohesin loader complex kollerin (NIPBL/MAU2), and that at mitotic exit it ensures proper levels of both MAU2 and cohesin itself on chromatin. In accordance with this newly described function in cohesin loading, we also show that NSD3 associates with chromatin in early anaphase, prior to the loading recruitment of MAU2 and RAD21, and that it then dissociates from chromatin when prophase begins. Going further, we also demonstrate that of the two NSD3 variants existing in somatic cells, it is the long isoform that is responsible for regulating kollerin and cohesin chromatin-loading, and that this isoform’s methyltransferase activity is required for efficient sister chromatid cohesion. Based on these observations, we propose that NSD3-dependent methylation contributes to sister chromatid cohesion by ensuring the proper recruitment of kollerin and thus loading of cohesin.