Implication of the VRK1 chromatin kinase in the signaling responses to DNA damage: a therapeutic target?

Abstract

DNA damage causes a local distortion of chromatin that triggers the sequential processes that participate in specific DNA repair mechanisms. This initiation of the repair response requires the involvement of a protein whose activity can be regulated by histones. Kinases are candidates to regulate and coordinate the connection between a locally altered chromatin and the response initiating signals that lead to identification of the type of lesion and the sequential steps required in specific DNA damage responses (DDR). This initiating kinase must be located in chromatin, and be activated independently of the type of DNA damage. We review the contribution of the Ser-Thr vaccinia-related kinase 1 (VRK1) chromatin kinase as a new player in the signaling of DNA damage responses, at chromatin and cellular levels, and its potential as a new therapeutic target in oncology. VRK1 is involved in the regulation of histone modifications, such as histone phosphorylation and acetylation, and in the formation of γH2AX, NBS1 and 53BP1 foci induced in DDR. Induction of DNA damage by chemotherapy or radiation is a mainstay of cancer treatment. Therefore, novel treatments can be targeted to proteins implicated in the regulation of DDR, rather than by directly causing DNA damage.

Keywords: 53BP1; DNA damage response; H2AX; Ionizing radiation; NBS1; Phosphorylation; VRK1; p53.

Fig. 1

VRK1 relation with transcription factors and DNA damage response proteins in chromatin

Fig. 2

Kinase activation induced by DNA damage and the regulation of p53 in G0/G1 cells. An enzyme (X) activated by VRK1, and that has not yet been identified, mediates the activation of ATM

Fig. 3

Downregulation of VRK1 by DRAM1 in the autophagic pathway induced by p53 and deactivation of p53 by phosphatases and ubiquitin ligases the proteasome in DNA damage response. Solid black lines represent the activation route. Dashed lines represent the downregulatory routes and each color represents a different route. Kinases: VRK1 and ATM. Phosphatases: WIP1 (wild-type P53-induced phosphatase 1) and DUSP4 (dual specificity phosphatase 4). DRAM1: damage-regulated autophagy modulator 1