The group of Pedro A. Lazo, researcher at the Institute of Molecular and Cellular Biology of Cancer, from CSIC and the University of Salamanca, is investigating the role of VRK1 kinase in response to cell damage and how it affects specific neurodegenerative diseases. Dr. Lazo, in his conference in IDIBELL last June, introduced some new developments relating cancer with VRK1, a chromatin kinase implicated in DNA damage responses, related to neurodegenerative diseases.
The VRK1 protein can be used as an indicator of DNA damage, and potentially could serve as cancer target. Dividing this protein the cells could become more sensitive to cancer treatments: the inhibition of the repair mechanism make the DNA strands more sensitive and, then, require less treatment, including chemotherapy and radiotherapy, to break them. "So patients could need less treatment and avoid certain side effects. VRK1 activation is independent of the type of DNA damage", said Lazo.
VRK1: new player controlling biological processes in cell division
Cell division requires the temporal and spatial coordination of several biological processes without which cell division would not be possible. These processes include the temporal coordination of DNA replication and chromosome segregation, regulation of nuclear envelope disassembly and assembly, chromatin condensation and Golgi fragmentation for its redistribution into daughter cells, among others. VRK1 plays an important coordinator role in these cell division processes, as its participation in signaling required for Golgi fragmentation late in the G2 phase, as part of a novel signaling pathway.
Cellular responses to DNA damage require the formation of protein complexes in a highly organized way. The complete molecular components that participate in the sequential signaling response to DNA damage (DDR) remain unknown. The researcher group lead by Lazo demonstrated that VRK1 in resting cells plays an important role in the formation of ionizing radiation-induced foci that assemble on the 53BP1 scaffold protein during DDR. The kinase VRK1 is activated by DNA double-strand breaks induced by ionizing radiation and specifically phosphorylates 53BP1. VRK1 knock-down resulted in the defective formation of 53BP1 foci in response to ionizing radiation, both in number and size. This observed effect on 53BP1 can be rescued with VRK1 mutants resistant to siRNA. VRK1 knockdown also prevented the activating phosphorylation of ATM, CHK2, and DNA-PK in response to ionizing radiation. VRK1 activation in response to DNA damage is a novel and early step in the signaling of mammalian DNA damage responses.
The VRK1 and neurodegenerative diseases
Furthermore, the research group is studying the importance of the kinase in certain neurodegenerative diseases, as muscle atrophy which could also be important in the development of Alzheimer's and amyotrophic lateral sclerosis (ALS). This process takes place in Cajal bodies, proteins located in the nucleus of neurons, where VRK1 regulates the formation and the stability of theses nuclear bodies. One of the objectives of the research group headed by Lazo is to know the regulatory mechanism that stimulates VRK1 to recover the function of these nuclear bodies. This could be performed by some manipulation, potentially beneficial to the patient and, to develop drugs to prevent these diseases in the future. However, Alzheimer's and ALS have a different mechanism, since it produces a protein aggregate. "If we manage to inhibit the protein aggregation regulating VRK1, we could minimize the development of these neurodegenerative diseases," concludes Lazo.