Abstract
Cellular responses to DNA damage require the formation of protein complexes in a highly organized fashion. The complete molecular components that participate in the sequential signaling response to DNA damage remain unknown. Here we demonstrate that vaccinia-related kinase 1 (VRK1) in resting cells plays an important role in the formation of ionizing radiation-induced foci that assemble on the 53BP1 scaffold protein during the DNA damage response. The kinase VRK1 is activated by DNA double strand breaks induced by ionizing radiation (IR) and specifically phosphorylates 53BP1 in serum-starved cells. VRK1 knockdown resulted in the defective formation of 53BP1 foci in response to IR both in number and size. This observed effect on 53BP1 foci is p53- and ataxia-telangiectasia mutated (ATM)-independent and can be rescued with VRK1 mutants resistant to siRNA. VRK1 knockdown also prevented the activating phosphorylation of ATM, CHK2, and DNA-dependent protein kinase in response to IR. VRK1 activation in response to DNA damage is a novel and early step in the signaling of mammalian DNA damage responses.
Highlights
The cellular response to DNA damage requires multiple signaling pathways to guarantee genomic stability
We determined whether vaccinia-related kinase 1 (VRK1) can be regulated by DNA damage as an indication of response to altered chromatin structure and determined its consequences on the response to DSBs detected by the formation of 53BP1 foci, a process that is independent of p53 [9]
We have identified that VRK1 is a kinase whose activity is enhanced in response to DNA damage and is a key component involved in channeling a specific response
Summary
The cellular response to DNA damage requires multiple signaling pathways to guarantee genomic stability. Results: Vaccinia-related kinase 1 (VRK1) is activated by ionizing radiation and required for formation of 53BP1 foci in response to DNA damage. The most common pathways in the DNA damage response (DDR) implicate protein phosphorylation by different kinases, such as ATM [1], ATR [2], and DNA-PK [3], which have been mostly studied in the context of cell division and cell cycle checkpoints [4]. It is known that the DNA damage response to DNA DSBs can be ATM-independent [13] This suggests that there are alternative kinases participating in DDR induced by ionizing radiation. We identify a novel role for VRK1 in responding to DSBs that directly connects the signal of damaged DNA to the DDR mediator protein 53BP1 in a p53- and ATM-independent mechanism
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