Vrk1-KO Mouse

Vrk1, or vaccinia-related kinase 1, is a nuclear Ser-Thr chromatin kinase. It phosphorylates several transcription factors, histones, and proteins in DNA damage response pathways. VRK1 is involved in regulating cell cycle entry, chromatin condensation in G2/M, Golgi fragmentation, Cajal body dynamics, and nuclear envelope assembly during mitosis. It also controls chromatin relaxation associated with histone acetylation and the non-homologous-end joining (NHEJ) DNA repair pathway [2].

In glioblastoma (GBM), a paralog-based synthetic lethality exists between VRK1 and VRK2. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated GBM cells leads to decreased activity of the downstream substrate barrier to autointegration factor (BAF), resulting in nuclear abnormalities, G2-M arrest, and DNA damage. Knockdown of VRK1 in VRK2-methylated GBM xenograft models inhibits tumor growth, suggesting VRK1 as a therapeutic target in VRK2-methylated GBM [1]. In ovarian cancer, VRK1 depletion promotes apoptosis, cell cycle arrest, and genomic instability by destabilizing DNA-PK, and enhances sensitivity to PARP inhibitor olaparib [4]. In zebrafish, vrk1-deficient models show mild microcephaly, impaired motor function, decreased cell proliferation, and defects in nuclear envelope and heterochromatin formation in the brain [3]. In ALS, the VRK1 R321C mutation in iPSC-derived motor neurons causes proteostatic imbalance and mitochondrial defects [5].

In conclusion, VRK1 is crucial for multiple cellular processes such as cell cycle regulation, chromatin remodeling, and DNA repair. Through gene knockout or knockdown models in various organisms, its roles in diseases like glioblastoma, ovarian cancer, neurodegenerative diseases have been revealed. These findings provide potential therapeutic targets for treating related diseases.

References:

1. Shields, Julie A, Meier, Samuel R, Bandi, Madhavi, Huang, Alan, Emmanuel, Natasha. . VRK1 Is a Synthetic-Lethal Target in VRK2-Deficient Glioblastoma. In Cancer research, 82, 4044-4057. doi:10.1158/0008-5472.CAN-21-4443. https://pubmed.ncbi.nlm.nih.gov/36069976/

2. Campillo-Marcos, Ignacio, García-González, Raúl, Navarro-Carrasco, Elena, Lazo, Pedro A. 2021. The human VRK1 chromatin kinase in cancer biology. In Cancer letters, 503, 117-128. doi:10.1016/j.canlet.2020.12.032. https://pubmed.ncbi.nlm.nih.gov/33516791/

3. Carrasco Apolinario, Magdeline E, Umeda, Ryohei, Teranishi, Hitoshi, Ohta, Keisuke, Hanada, Reiko. 2023. Behavioral and neurological effects of Vrk1 deficiency in zebrafish. In Biochemical and biophysical research communications, 675, 10-18. doi:10.1016/j.bbrc.2023.07.005. https://pubmed.ncbi.nlm.nih.gov/37429068/

4. Kim, Do Yeon, Yun, Hyeseon, You, Ji-Eun, Koh, Dong-In, Jin, Dong-Hoon. 2024. Inactivation of VRK1 sensitizes ovarian cancer to PARP inhibition through regulating DNA-PK stability. In Experimental cell research, 438, 114036. doi:10.1016/j.yexcr.2024.114036. https://pubmed.ncbi.nlm.nih.gov/38614421/

5. Oliveira, D, Assoni, A F, Alves, L M, Ferrari, M R, Zatz, M. 2024. ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons. In Neurobiology of disease, 198, 106540. doi:10.1016/j.nbd.2024.106540. https://pubmed.ncbi.nlm.nih.gov/38806131/