Request Demo

Last update 23 Jan 2025

TP53RK

Last update 23 Jan 2025

Basic Info

Synonyms

Atypical serine/threonine protein kinase TP53RK, BUD32, C20orf64

+ [11]

Introduction

Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine (PubMed:22912744, PubMed:27903914). The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37 (PubMed:22912744, PubMed:27903914). TP53RK has ATPase activity in the context of the EKC/KEOPS complex and likely plays a supporting role to the catalytic subunit OSGEP (By similarity). Atypical protein kinase that phosphorylates 'Ser-15' of p53/TP53 protein and may therefore participate in its activation (PubMed:11546806).

Drugs associated with TP53RK

Alpha ketoglutarate

Target

Reactive oxygen species x TP53RK

Mechanism

Reactive oxygen species stimulants [+1]

Active Org.

Shandong University

Originator Org.

Institute of Nuclear Medicine & Allied Sciences

Active Indication

Diffuse Large B-Cell Lymphoma

Inactive Indication

Poisoning

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with TP53RK

CTRI/2013/02/003355

/ RecruitingPhase 2

An open labeled, comparative, step-up phase-2 clinical study to assess bioavailability and efficacy of sodium alpha-ketoglutarate infusion injection in patients with cyanide overload

Start Date31 Aug 2012

Sponsor / Collaborator

Defence Research & Development Establishment

CTRI/2013/01/003331

/ RecruitingPhase 2

A phase-II open labeled, comparative, field study to assess efficacy of oral sodium alpha-ketoglutarate in treating cyanide poisoning

Start Date31 Aug 2012

Sponsor / Collaborator

Defence Research & Development Establishment

CTRI/2013/02/003356

/ RecruitingPhase 2

An open labeled, comparative, step-up phase-II clinical study to assess deposition and efficacy of sodium alpha-ketoglutarate nebulization fluid (submicron-sized) in management of hydrogen cyanide, methyl isocyanate (MIC) toxicity and ammonia gas exposure

Start Date31 Aug 2012

Sponsor / Collaborator

Defence Research & Development Establishment

100 Clinical Results associated with TP53RK

100 Translational Medicine associated with TP53RK

0 Patents (Medical) associated with TP53RK

Literatures (Medical) associated with TP53RK

08 May 2024·Nucleic Acids Research

Molecular basis of A. thaliana KEOPS complex in biosynthesizing tRNA t6A

Article

Author: Zhu, Li ; Duan, Lei ; Zhang, Wenhua ; Jin, Mengqi ; Su, Chenchen ; Zheng, Xinxing ; Sun, Yongtao

AbstractIn archaea and eukaryotes, the evolutionarily conserved KEOPS is composed of four core subunits―Kae1, Bud32, Cgi121 and Pcc1, and a fifth Gon7/Pcc2 that is found in fungi and metazoa. KEOPS cooperates with Sua5/YRDC to catalyze the biosynthesis of tRNA N6-threonylcarbamoyladenosine (t6A), an essential modification needed for fitness of cellular organisms. Biochemical and structural characterizations of KEOPSs from archaea, yeast and humans have determined a t6A-catalytic role for Kae1 and auxiliary roles for other subunits. However, the precise molecular workings of KEOPSs still remain poorly understood. Here, we investigated the biochemical functions of A. thaliana KEOPS and determined a cryo-EM structure of A. thaliana KEOPS dimer. We show that A. thaliana KEOPS is composed of KAE1, BUD32, CGI121 and PCC1, which adopts a conserved overall arrangement. PCC1 dimerization leads to a KEOPS dimer that is needed for an active t6A-catalytic KEOPS–tRNA assembly. BUD32 participates in direct binding of tRNA to KEOPS and modulates the t6A-catalytic activity of KEOPS via its C-terminal tail and ATP to ADP hydrolysis. CGI121 promotes the binding of tRNA to KEOPS and potentiates the t6A-catalytic activity of KEOPS. These data and findings provide insights into mechanistic understanding of KEOPS machineries.

30 Jan 2024·mSphere

Sua5 catalyzing universal t ⁶ A tRNA modification is responsible for multifaceted functions of the KEOPS complex in Cryptococcus neoformans

Article

Author: Hyeon, Hana ; Bahn, Yong-Sun ; Choi, Yeseul ; Lee, Kangseok

ABSTRACT The N 6 -threonylcarbamoyl adenosine (t 6 A) tRNA modification is critical for ensuring translation fidelity across three domains of life. Our prior work highlighted the KEOPS complex, organized in a Pcc1-Kae1-Bud32-Cgi121 linear arrangement, not only serves an evolutionarily conserved role in t 6 A tRNA modification but also exerts diverse functional impacts on pathobiological characteristics in Cryptococcus neoformans , a leading cause of fungal meningitis worldwide. However, the extent to which the pleiotropic functions of the KEOPS complex are specifically tied to tRNA modification remains uncertain. To address this, we undertook a functional characterization of Sua5, responsible for generating the precursor threonylcarbamoyl-adenylate (TC-AMP) for t 6 A tRNA modification, using a reverse genetics approach. Comparative phenotypic analyses with KEOPS mutants revealed that Sua5 plays a vital role in multiple cellular processes, such as t 6 A tRNA modification, growth, sexual development, stress response, and virulence factor production, thus reflecting the multifaceted functions of the KEOPS complex. In support of this, sua5 Δ bud32 Δ double mutants showed phenotypes comparable to those of the corresponding single mutants. Intriguingly, a SUA5 allele lacking a mitochondria targeting sequence ( SUA5 MTSΔ ) was sufficient to restore the wild-type phenotypes in the sua5 Δ mutant, suggesting that Sua5’s primary functional locus may be cytosolic, akin to the KEOPS complex. Further supporting this, the deletion of Qri7, a mitochondrial paralog of Kae1, had no discernible phenotypic impact on C. neoformans . We concluded that cytosolic t 6 A tRNA modifications, orchestrated by Sua5 and the KEOPS complex, are central to the regulation of diverse pathobiological functions in C. neoformans . IMPORTANCE Understanding cellular functions at the molecular level is crucial for advancing disease treatments. Our research reveals a critical connection between the KEOPS complex and Sua5 in Cryptococcus neoformans , a significant cause of fungal meningitis. While the KEOPS complex is known for its versatile roles in cellular processes, Sua5 is specialized in t 6 A tRNA modification. Our key finding is that the diverse roles of the KEOPS complex, ranging from cell growth and stress response to virulence, are fundamentally linked to its function in t 6 A tRNA modification. This conclusion is supported by the remarkable similarities between the impacts of Sua5 and KEOPS on these processes, despite their roles in different steps of the t 6 A modification pathway. This newfound understanding deepens our insight into fungal biology and opens new avenues for developing potential therapies against dangerous fungal diseases.

09 Nov 2023·Cancer Research Communications

Enitociclib, a Selective CDK9 Inhibitor, Induces Complete Regression of MYC+ Lymphoma by Downregulation of RNA Polymerase II Mediated Transcription

Article

Author: Izumi, Raquel ; Frigault, Melanie M ; Hamdy, Ahmed ; Huang, Xin ; Johnson, Amy J ; Wong, Harvey ; Stelte-Ludwig, Beatrix ; Birkett, Joseph ; Mithal, Arushi ; Mandava, Vinay

AbstractDouble-hit diffuse large B-cell lymphoma (DH-DLBCL) is an aggressive, and often refractory, type of B-cell non–Hodgkin lymphoma (NHL) characterized by rearrangements in MYC and BCL2. Cyclin-dependent kinase 9 (CDK9) regulates transcriptional elongation and activation of transcription factors, including MYC, making it a potential targeted approach for the treatment of MYC+ lymphomas. Enitociclib is a well-tolerated and clinically active CDK9 inhibitor leading to complete metabolic remissions in 2 of 7 patients with DH-DLBCL treated with once weekly 30 mg intravenous administration. Herein, we investigate the pharmacodynamic effect of CDK9 inhibition in preclinical models and in blood samples from patients [DH-DLBCL (n = 10) and MYC+ NHL (n = 5)] treated with 30 mg i.v. once weekly enitociclib. Enitociclib shows significant regulation of RNA polymerase II Ser2 phosphorylation in a MYC-amplified SU-DHL-4 cell line and depletion of MYC and antiapoptosis protein MCL1 in SU-DHL-4 and MYC-overexpressing SU-DHL-10 cell lines in vitro. Tumor growth inhibition reaching 0.5% of control treated SU-DHL-10 xenografts is achieved in vivo and MYC and MCL1 depletion as well as evidence of apoptosis activation after enitociclib treatment is demonstrated. An unbiased analysis of the genes affected by CDK9 inhibition in both cell lines demonstrates that RNA polymerase II and transcription pathways are primarily affected and novel enitociclib targets such as PHF23 and TP53RK are discovered. These findings are recapitulated in blood samples from enitociclib-treated patients; while MYC downregulation is most robust with enitociclib treatment, other CDK9-regulated targets may be MYC independent delivering a transcriptional downregulation via RNA polymerase II.Significance:MYC+ lymphomas are refractory to standard of care and novel treatments that downregulate MYC are needed. The utility of enitociclib, a selective CDK9 inhibitor in this patient population, is demonstrated in preclinical models and patients. Enitociclib inhibits RNA polymerase II function conferring a transcriptional shift and depletion of MYC and MCL1. Enitociclib intermittent dosing downregulates transcription factors including MYC, providing a therapeutic window for durable responses in patients with MYC+ lymphoma.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

TP53RK

Basic Info

Related

Analysis