Macro Histone H2A1.2 (MacroH2A1) Protein Suppresses Mitotic Kinase VRK1 during Interphase

Kim, Wanil; Chakraborty, Goutam; Kim, Sangjune; Shin, Joon; Park, Choon-ho; Jeong, Minwoo; Bharatham, Nagakumar; Yoon, Ho Sup; Kim, Kyong‐Tai

doi:10.1074/jbc.m111.281709

Cited by 48 publications

(67 citation statements)

References 30 publications

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“…VRK1 kinase activity is regulated by the folding of its C-terminal region [29,49] that results in a conformational change in native protein that is recognized by a specific monoclonal antibody (1B5) [45]. Previous work has shown this structural change in cells upon DNA damage response to ionizing radiation [31].…”

Section: The Basal Vrk1-p53 Complex Is Immediately Activated In Respomentioning

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 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].…”

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%

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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: The Basal Vrk1-p53 Complex Is Immediately Activated In Respomentioning

confidence: 99%

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

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].…”

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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“…This phosphorylation was confirmed in vitro and in HEK293 cells, where overexpression of Haspin caused hyper-phosphorylation of Histone macroH2A on Ser137, the latter being inhibited by 5-ITu. It has also been reported that the macro domain of Histone macroH2A controls the levels of Ser10 and Thr3 phosphorylation of histone H3 in human cells and would be involved in controlling chromatin condensation [21,22]. The functionality of Haspin in these mechanisms remains to be confirmed.…”

Section: Haspin Substratesmentioning

confidence: 98%

The Mitotic Protein Kinase Haspin and Its Inhibitors

Feizbakhsh¹,

Place²,

Fant³

et al. 2017

Protein Phosphorylation

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Haspin is an atypical serine/threonine protein kinase essential to mitosis. Unlike other protein kinases, its kinase domain does not require phosphorylation in order to be activated and bears very high substrate specificity and selectivity. Few substrates have been identified so far. Haspin phosphorylation on threonine 3 of Histone H3 from prophase to anaphase participates to centromeric Aurora B localization and ensures proper kinetochore-microtubule attachment. Haspin is also involved in the maintenance of centromeric cohesion and the mitotic spindle. Inhibitors have been developed and provided tools to dissect Haspin function. The kinase is now considered as a potential therapeutic target against cancer. We discuss here the latest findings on this essential mitotic protein.

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Crystal structure of human vaccinia‐related kinase 1 in complex with AMP‐PNP, a non‐hydrolyzable ATP analog

Ngow

Rajan

et al. 2018

Protein Science

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Vaccinia‐related kinase 1 (VRK1), a serine/threonine mitotic kinase, is widely over‐expressed in dividing cells and regarded as a cancer drug target primarily due to its function as an early response gene in cell proliferation. However, the mechanism of VRK1 phosphorylation and substrate activation is not well understood. More importantly even the molecular basis of VRK1 interaction with its cofactor, adenosine triphosphate (ATP), is unavailable to‐date. As designing specific inhibitors remains to be the major challenge in kinase research, such a molecular understanding will enable us to design ATP‐competitive specific inhibitors of VRK1. Here we report the molecular characterization of VRK1 in complex with AMP‐PNP, a non‐hydrolyzable ATP‐analog, using NMR titration followed by the co‐crystal structure determined upto 2.07 Å resolution. We also carried out the structural comparison of the AMP‐PNP bound‐form with its apo and inhibitor‐bound counterparts, which has enabled us to present our rationale toward designing VRK1‐specific inhibitors.

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Macro Histone H2A1.2 (MacroH2A1) Protein Suppresses Mitotic Kinase VRK1 during Interphase

Cited by 48 publications

References 30 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

The Mitotic Protein Kinase Haspin and Its Inhibitors

Crystal structure of human vaccinia‐related kinase 1 in complex with AMP‐PNP, a non‐hydrolyzable ATP analog

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