VRK1-mediated regulation of Tip60/KAT5 acetyltransferase during DDR
Centro de Investigación del Cáncer (CIC-IBMCC)
The epigenome plays a crucial role on cell differentiation and response to different environmental and cellular conditions, including DNA damage. For that purpose, it can mediate important processes such as transcription or DNA damage response (DDR). Therefore, the modulation of different epigenetic marks must be a tightly controlled process, and its deregulation is involved in the onset of different diseases, including cancer. In this context, one of the most important mechanisms of epigenome regulation consists on regulating the activity of the epigenetic enzymes through post-translational modifications. For instance, the lysine acetyltransferase 5 (KAT5, also known as Tip60) is phosphorylated by different kinases in order to modulate the epigenetic pattern throughout the cell cycle. In addition, Tip60 also plays crucial roles during DDR, including the acetylation of the lysine 16 of histone 4 (H4K16), essential for chromatin decompaction, or acetylation of ATM. To our knowledge, nonetheless, any mechanism of Tip60 modulation and activation in the context of DNA damage has been described.
Herein, we describe a novel mechanism of Tip60 regulation mediated by VRK1 in response to DNA damage. We have shown that VRK1 phosphorylates Tip60 after DNA damage induction. This leads not only to Tip60 autoacetylation and subsequent activation, but also to an increase of the protein stability and its accumulation around chromatin. These three phenomena would jointly contribute to the development of Tip60 activity during DDR.