Vrk1, a nuclear Ser-Thr chromatin kinase, is distributed in nucleoplasm and chromatin. It phosphorylates several transcription factors, histones, and proteins involved in DNA damage response pathways. VRK1 regulates cell cycle entry, chromatin condensation in G2/M, Golgi fragmentation, Cajal body dynamics, and nuclear envelope assembly during mitosis. It also controls chromatin relaxation related to histone acetylation and the non-homologous-end-joining (NHEJ) DNA repair pathway [2,3].

Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated glioblastoma cells led to decreased activity of the downstream substrate barrier to autointegration factor (BAF), resulting in nuclear abnormalities, G2-M arrest, and DNA damage, indicating a synthetic-lethal interaction between VRK1 and VRK2 in glioblastoma [1]. In VRK2-methylated glioblastoma cell line-derived xenograft and patient-derived xenograft models, knockdown of VRK1 inhibited tumor growth [1]. In ovarian cancer, VRK1 depletion promoted apoptosis, cell cycle arrest, and enhanced sensitivity to a PARP inhibitor by destabilizing DNA-PK [5]. In zebrafish, vrk1-deficient models showed mild microcephaly, impaired motor function, decreased cell proliferation, and defects in nuclear envelope and heterochromatin formation in the brain [4]. In iPSC-derived motor neurons, an ALS-associated VRK1 mutation caused proteostatic imbalance and mitochondrial defects [6].

In summary, Vrk1 plays crucial roles in cell proliferation, chromatin stability, DNA damage response, and Cajal body regulation. Studies using gene knockdown or knockout models in various organisms, such as zebrafish and in vitro cell models for glioblastoma and ovarian cancer, have revealed its functions in cancer and neurodegenerative diseases. These models contribute to understanding the role of Vrk1 in specific biological processes and disease conditions, providing potential therapeutic targets for related diseases.