Halogenated imidazole derivatives block RNA polymerase II elongation along mitogen inducible genes

Mikula, Michał; Hanusek, Karolina; Paziewska, Agnieszka; Dzwonek, Artur; Rubel, Tymon; Bomsztyk, Karol; Ostrowski, Jerzy

doi:10.1186/1471-2199-11-4

Cited by 9 publications

(11 citation statements)

References 46 publications

(58 reference statements)

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“…However, several experimental limitations are associated with these conflicting studies. These include the exclusive use of cell models, use of CK2 inhibitors with poor selectivity and high toxicity (Mikula et al 2010), and absence of genetic evidence to demonstrate the specificity of the inhibitors used as well as the differential contribution between CK2α or CK2α’ subunits. We have now confirmed that CK2α’ upregulation in HD is detrimental and contributes to HD onset and progression.…”

Section: Discussionmentioning

confidence: 99%

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

Zarate

Cuccu

et al. 2020

Preprint

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Huntington′s Disease (HD) is a neurodegenerative disorder caused a polyglutamine expansion in the HTT protein. This mutation causes HTT misfolding and aggregation, preferentially affecting neurons of the basal ganglia. Other aggregation-prone proteins like alpha-synuclein (α-syn), mostly associated with Parkinson′s disease (PD), has recently been involved in motor deficits in HD, but its mechanism of action is unknown. Here we showed that α-syn serine 129 phosphorylation (α-syn-pS129), a posttranslational modification linked to α-synucleinopathy, is highly phosphorylated in the brain of symptomatic zQ175 HD mice. We demonstrated that such phosphorylation is mediated by Protein Kinase CK2 alpha prime (CK2α′), which is preferentially induced in striatal neurons in HD. Knocking out one allele of CK2α′ in zQ175 mice decreased α-syn-pS129 in the striatum and ameliorated several HD-like symptoms including neuroinflammation, transcriptional alterations, excitatory synaptic transmission dysfunction and motor deficits. Our data suggests CK2α′-mediated synucleinopathy as a key molecular mechanism for striatal neurons degeneration in HD.

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Section: Discussionmentioning

confidence: 99%

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

Zarate

Cuccu

et al. 2020

Preprint

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“…The adenosine analog 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole (DRB) inhibits the Pol II Ser-2 carboxyl-terminal domain kinase, CDK9, a component of the positive transcription elongation factor (P-TEF-b) (62)(63)(64). We used DRB to explore the role of Pol II elongation on the recruitment of ERK cascade components to the EGR-1 gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

Direct Recruitment of ERK Cascade Components to Inducible Genes Is Regulated by Heterogeneous Nuclear Ribonucleoprotein (hnRNP) K

Mikula

Bomsztyk

2011

Journal of Biological Chemistry

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Components of the ERK cascade are recruited to genes, but it remains unknown how they are regulated at these sites. The RNA-binding protein heterogeneous nuclear ribonucleoprotein (hnRNP) K interacts with kinases and is found along genes including the mitogen-inducible early response gene EGR-1. Here, we used chromatin immunoprecipitations to study co-recruitment of hnRNP K and ERK cascade activity along the EGR-1 gene. These measurements revealed that the spatiotemporal binding patterns of ERK cascade transducers (GRB2, SOS, B-Raf, MEK, and ERK) at the EGR-1 locus resemble both hnRNP K and RNA polymerase II (Pol II). Inhibition of EGR-1 transcription with either serum-responsive factor knockdown or 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole altered recruitment of all of the above ERK cascade components along this locus that mirrored the changes in Pol II and hnRNP K profiles. siRNA knockdown of hnRNP K decreased the levels of active MEK and ERK at the EGR-1, changes associated with decreased levels of elongating pre-mRNA and less efficient splicing. The hnRNP K dependence and pattern of ERK cascade activation at the c-MYC locus were different from at EGR-1. Ribonucleoprotein immunoprecipitations revealed that hnRNP K was associated with the EGR-1 but not c-MYC mRNAs. These data suggest a model where Pol II transcription-driven recruitment of hnRNP K along the EGR-1 locus compartmentalizes activation of the ERK cascade at these genes, events that regulate synthesis of mature mRNA.

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“…Chromatin cross-linking and cell harvesting were performed as previously described. 16 Chromatin was sheared for seven rounds of 20 s (1 s pulse, 0.5 s gap) on-off pulses with a 500-Watt Ultrasonic Processor (Cole-Parmer Instrument Co., Vernon Hills, IL, USA) equipped with a microtip and set to 30% of maximum power. Chromatin immunoprecipitation (ChIP) assays were performed using the Matrix-ChIP platform as previously described.…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Analysis of the Palindromic Motif TCTCGCGAGA: A Regulatory Element of the HNRNPK Promoter

et al. 2010

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Definitive identification of promoters, their cis-regulatory motifs, and their trans-acting proteins requires experimental analysis. To define the HNRNPK promoter and its cognate DNA–protein interactions, we performed a comprehensive study combining experimental approaches, including luciferase reporter gene assays, chromatin immunoprecipitations (ChIP), electrophoretic mobility shift assays (EMSA), and mass spectrometry (MS). We discovered that out of the four potential HNRNPK promoters tested, the one containing the palindromic motif TCTCGCGAGA exhibited the highest activity in a reporter system assay. Although further EMSA and MS analyses, performed to uncover the identity of the palindrome-binding transcription factor, did identify a complex of DNA-binding proteins, neither method unambiguously identified the pertinent direct trans-acting protein(s). ChIP revealed similar chromatin states at the promoters with the palindromic motif and at housekeeping gene promoters. A ChIP survey showed significantly higher recruitment of PARP1, a protein identified by MS as ubiquitously attached to DNA probes, within heterochromatin sites. Computational analyses indicated that this palindrome displays features that mark nucleosome boundaries, causing the surrounding DNA landscape to be constitutively open. Our strategy of diverse approaches facilitated the direct characterization of various molecular properties of HNRNPK promoter bearing the palindromic motif TCTCGCGAGA, despite the obstacles that accompany in vitro methods.

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Halogenated imidazole derivatives block RNA polymerase II elongation along mitogen inducible genes

Cited by 9 publications

References 46 publications

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

Direct Recruitment of ERK Cascade Components to Inducible Genes Is Regulated by Heterogeneous Nuclear Ribonucleoprotein (hnRNP) K

Comprehensive Analysis of the Palindromic Motif TCTCGCGAGA: A Regulatory Element of the HNRNPK Promoter

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