VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage

Abstract

All types of DNA damage cause a local alteration and relaxation of chromatin structure. Sensing and reacting to this initial chromatin alteration is a necessary trigger for any type of DNA damage response (DDR). In this context, chromatin kinases are likely candidates to participate in detection and reaction to a locally altered chromatin as a consequence of DNA damage and, thus, initiate the appropriate cellular response. In this work, we demonstrate that VRK1 is a nucleosomal chromatin kinase and that its depletion causes loss of histones H3 and H4 acetylation, which are required for chromatin relaxation, both in basal conditions and after DNA damage, independently of ATM. Moreover, VRK1 directly and stably interacts with histones H2AX and H3 in basal conditions. In response to DNA damage induced by ionizing radiation, histone H2AX is phosphorylated in Ser139 by VRK1. The phosphorylation of H2AX and the formation of gH2AX foci induced by ionizing radiation (IR), are prevented by VRK1 depletion and are rescued by kinase-active, but not kinase-dead, VRK1. In conclusion, we found that VRK1 is a novel chromatin component that reacts to its alterations and participates very early in DDR, functioning by itself or in cooperation with ATM.

Oncogenic Sox2 regulates and cooperates with VRK1 in cell cycle progression and differentiation

“…At this stage Sox2 connects with VRK1, a chromatin kinase, associated to several aspect of cell proliferation22 as well to chromatin remodeling16. Thus, the regulation of VRK1 gene by Sox2 is fully consistent with a role for VRK1 as an initiator of cell proliferation17.…”

VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis

“…VRK1 is mostly a chromatin kinase and regulates histones [9, 26], but is also present in other complexes of nucleic acids, including RNA, and nucleoproteins, as exemplified by the complex with coilin [27, 28], the scaffold protein of Cajal bodies [29]. It is possible that VRK1 plays complementary roles, as a key regulator of chromatin dynamics in different situations ranging from relaxation [26] to compaction [9] at the entry of mitosis.…”

“…It is possible that VRK1 plays complementary roles, as a key regulator of chromatin dynamics in different situations ranging from relaxation [26] to compaction [9] at the entry of mitosis. In turn, AURKB is more restricted to chromosome dynamics during mitosis, since chromatin organization affects chromosome structure.…”

Comparative Interactomes of VRK1 and VRK3 with Their Distinct Roles in the Cell Cycle of Liver Cancer

“…VRK1 phosphorylates barrier-to-autointegration factor (BAF), which induces the disassembly of a complex containing chromatin, LEM proteins, and BAF (Gorjanacz et al, 2007; Nichols et al, 2006). Furthermore, VRK1 binds and phosphorylates several transcription factors such as ATF2 (Sevilla et al, 2004b), CREB1 (Kang et al, 2008), and c-Jun (Sevilla et al, 2004a) and histone proteins such as mitotic histone H3 (Kang et al, 2007), macroH2A1 (Kim et al, 2012), and H2AX (Salzano et al, 2015). In addition, HnRNP A1 is phosphorylated by VRK1 to stimulate telomerase (Choi et al, 2012).…”