Vaccinia-related Kinase 1 (VRK1) Is an Upstream Nucleosomal Kinase Required for the Assembly of 53BP1 Foci in Response to Ionizing Radiation-induced DNA Damage

Sanz-García, Marta; Monsalve, Diana M.; Sevilla, Ana; Lazo, Pedro A.

doi:10.1074/jbc.m112.353102

Cited by 59 publications

(156 citation statements)

References 72 publications

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“…Based on observations showing that VRK1 directly phosphorylates p53 in Thr-18 [7]; that its knockdown results in the loss of this phosphorylation [31,33] and that endogenous p53 and VRK1 proteins co-localize in nuclei of non-damaged [8], we asked whether p53 and VRK1 were able to form a stable protein complex. To detect this potential VRK1-p53 complex, reciprocal immunoprecipitation of endogenous proteins were performed in HEK293T cells and both proteins, VRK1 and p53, were detected (Fig.…”

Section: Vrk1 Stably Interacts With P53 Forming a Basal Protein Complexmentioning

confidence: 99%

“…The VRK1 C-terminal region (residues 275-396) is characterized by its low complexity [49] and its flexibility [49]. This C-terminal region has been described to interact with several proteins and to play a regulatory role [28,29,31]. For these reasons, next we analysed if this VRK1 region was binding to p53 by performing pull-down assays and with two different GST-VRK1 constructs [44]; full-length VRK1 (residues 1-396) and VRK1DN comprising the C-terminus (residues 267-396) (Fig.…”

Section: Vrk1 Stably Interacts With P53 Forming a Basal Protein Complexmentioning

confidence: 99%

“…Moreover, VRK1 positively correlates with the proliferation phenotype in human head and neck [37] and lung cancers [34,38], and in breast cancer xenographs it also affects proliferation [39]. In addition, VRK1 kinase activity is enhanced in response to DNA damage and is an early participant necessary for the formation of 53BP1 foci in response to DNA double-strand breaks induced by ionizing radiation, in both resting and dividing cells [31]. In murine gene-trap models, VRK1 deficiency results in sterility due to either meiotic defects in females or by affecting maintenance of spermatogonial stem cells prior to meiosis in males [40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

“…VRK1, the most abundant Ser-Thr kinase in nuclei [23], is a nucleosomal/chromatin kinase that can form complexes and phosphorylate several transcription factors [24][25][26], histones [18,[27][28][29] and other chromatin proteins [30,31]. Moreover, VRK1 kinase activity can also be regulated by these proteins interactions, including those with histones [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, VRK1 kinase activity can also be regulated by these proteins interactions, including those with histones [28][29][30]. VRK1 is also activated by DNA damage [31]. Therefore, VRK1 is a good candidate to participate in an early response mechanism to DNA damage.…”

Section: Introductionmentioning

confidence: 99%

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VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

et al. 2014

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a b s t r a c t DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1-p53 basal complex is an early-warning system for immediate cellular responses to DNA damage. Structured summary of protein interactions:VRK1 physically interacts with p53 by anti bait coimmunoprecipitation (1, 2, 3, 4) VRK1 physically interacts with p53 by pull down (1,2,3)

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Section: Vrk1 Stably Interacts With P53 Forming a Basal Protein Complexmentioning

confidence: 99%

Section: Vrk1 Stably Interacts With P53 Forming a Basal Protein Complexmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

et al. 2014

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VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy

Marcos¹,

Martín-Doncel

Morejón‐García

et al. 2020

Ann Clin Transl Neurol

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Background Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous. Patient and methods In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole‐exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein. Results A novel homozygous recessive mutation in the human VRK1 gene, coding for a chromatin kinase, causing a substitution (c.637T > C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C‐terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild‐type VRK1. Conclusion The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation.

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Vrk1

Cantarero¹,

Moura²,

Salzano³

et al. 2016

Encyclopedia of Signaling Molecules

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Vaccinia-related Kinase 1 (VRK1) Is an Upstream Nucleosomal Kinase Required for the Assembly of 53BP1 Foci in Response to Ionizing Radiation-induced DNA Damage

Cited by 59 publications

References 72 publications

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy

Vrk1

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