SETD6 methyltransferase protects cells from multinucleation post replication-stress through Aurora-B methylation
2National Institute for Biotechnology in the Negev, Ben Gurion University, Israel
Lysine methylation of non-histone proteins is arising in the recent years as a key player in several housekeeping signaling pathways. SETD6 lysine methylatransferase was previously shown to participate in essential cellular processes, such as the NFkB pathway, Wnt signaling pathway, mitosis and many more.
Here we show that SETD6 is involved in cytokinesis regulation. SETD6 knockout HeLa cells present a remarkable increase in percentage of chromatin bridges and moreover, upon replication stress, these SETD6 depleted cells showed a high tendency to multinucleate. This raised the possibility for a direct or in-direct involvement of SETD6 in cytokinesis, a step in which the two daughter cells are divided after mitosis.
In a proteomic screen to identify novel SETD6 substrates, we previously identified 118 proteins that were methylated by SETD6. One of these newly identified SETD6 substrates was Aurora-B kinase, which is known as an essential cytokinesis regulator. We found that SETD6 binds and methylates Aurora-B in-vitro and in cells and that this methylation occurs on two adjacent lysine residues. Aurora-B methylation by SETD6 increases upon replication stress but is abolished when the two lysine methylation targets are substituted.
Multinuclear cells are often observed in tumors. It would be only reasonable to hypothesize that Aurora-B methylation by SETD6 carries meaningful implications on tumorigenic cellular pathways.