Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular Del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, 37007 Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, Spain.
Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular Del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, 37007 Salamanca, Spain.
Cancer Lett. 2021 Apr 10;503:117-128. doi: 10.1016/j.canlet.2020.12.032. Epub 2021 Jan 29.
VRK1 is a nuclear Ser-Thr chromatin kinase that does not mutate in cancer, and is overexpressed in many types of tumors and associated with a poor prognosis. Chromatin VRK1 phosphorylates several transcription factors, including p53, histones and proteins implicated in DNA damage response pathways. In the context of cell proliferation, VRK1 regulates entry in cell cycle, chromatin condensation in G2/M, Golgi fragmentation, Cajal body dynamics and nuclear envelope assembly in mitosis. This kinase also controls the initial chromatin relaxation associated with histone acetylation, and the non-homologous-end joining (NHEJ) DNA repair pathway, which involves sequential steps such as γH2AX, NBS1 and 53BP1 foci formation, all phosphorylated by VRK1, in response to ionizing radiation or chemotherapy. In addition, VRK1 can be an alternative target for therapies based on synthetic lethality strategies. Therefore, VRK1 roles on proliferation have a pro-tumorigenic effect. Functions regulating chromatin stability and DNA damage responses have a protective anti-tumor role in normal cells, but in tumor cells can also facilitate resistance to genotoxic treatments.
VRK1 是一种核 Ser-Thr 染色质激酶，在癌症中不会发生突变，在许多类型的肿瘤中过度表达，并与预后不良相关。染色质 VRK1 磷酸化多种转录因子，包括 p53、组蛋白和参与 DNA 损伤反应途径的蛋白质。在细胞增殖的情况下，VRK1 调节细胞周期进入、G2/M 期染色质浓缩、高尔基体碎片化、Cajal 体动力学和有丝分裂中的核膜组装。这种激酶还控制与组蛋白乙酰化相关的初始染色质松弛，以及非同源末端连接 (NHEJ) DNA 修复途径，该途径涉及一系列步骤，如 γH2AX、NBS1 和 53BP1 焦点形成，所有这些都被 VRK1 磷酸化，以响应电离辐射或化疗。此外，VRK1 可以成为基于合成致死性策略的治疗的替代靶标。因此，VRK1 在增殖中的作用具有促进肿瘤发生的效果。调节染色质稳定性和 DNA 损伤反应的功能在正常细胞中具有保护抗肿瘤作用，但在肿瘤细胞中也可以促进对遗传毒性治疗的耐药性。
