Last update 19 Sep 2024

CMTR1

Last update 19 Sep 2024

Basic Info

Synonyms

cap methyltransferase 1, Cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 1, Cap1 2'O-ribose methyltransferase 1

+ [8]

Introduction

S-adenosyl-L-methionine-dependent methyltransferase that mediates mRNA cap1 2'-O-ribose methylation to the 5'-cap structure of mRNAs. Methylates the ribose of the first nucleotide of a m(7)GpppG-capped mRNA and small nuclear RNA (snRNA) to produce m(7)GpppRm (cap1). Displays a preference for cap0 transcripts. Cap1 modification is linked to higher levels of translation. May be involved in the interferon response pathway.

Drugs associated with CMTR1

Trifluoromethyl-tubercidin

Target

CMTR1 x PB2

Mechanism

CMTR1 modulators [+1]

Active Org.

University of Bonn

Originator Org.

University of Bonn

Active Indication

Influenza A virus infection

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CMTR1

100 Translational Medicine associated with CMTR1

0 Patents (Medical) associated with CMTR1

Literatures (Medical) associated with CMTR1

01 Jul 2024·Cell Reports

CK2 phosphorylation of CMTR1 promotes RNA cap formation and influenza virus infection

Article

Author: Roberts, Edward W ; Pirillo, Chiara ; Hepburn, Lydia A ; Lukoszek, Radoslaw ; Hughes, David J ; Cowling, Victoria H ; Inesta-Vaquera, Francisco ; Brett, Natasha J M ; Liang, Shang

The RNA cap methyltransferase CMTR1 methylates the first transcribed nucleotide of RNA polymerase II transcripts, impacting gene expression mechanisms, including during innate immune responses. Using mass spectrometry, we identify a multiply phosphorylated region of CMTR1 (phospho-patch [P-Patch]), which is a substrate for the kinase CK2 (casein kinase II). CMTR1 phosphorylation alters intramolecular interactions, increases recruitment to RNA polymerase II, and promotes RNA cap methylation. P-Patch phosphorylation occurs during the G1 phase of the cell cycle, recruiting CMTR1 to RNA polymerase II during a period of rapid transcription and RNA cap formation. CMTR1 phosphorylation is required for the expression of specific RNAs, including ribosomal protein gene transcripts, and promotes cell proliferation. CMTR1 phosphorylation is also required for interferon-stimulated gene expression. The cap-snatching virus, influenza A, utilizes host CMTR1 phosphorylation to produce the caps required for virus production and infection. We present an RNA cap methylation control mechanism whereby CK2 controls CMTR1, enhancing co-transcriptional capping.

01 Jun 2024·Current Biology

CMTR-1 RNA methyltransferase mutations activate widespread expression of a dopaminergic neuron-specific mitochondrial complex I gene

Article

Author: Meisel, Joshua D ; Mootha, Vamsi K ; Wiesenthal, Presli P ; Ruvkun, Gary

The mitochondrial proteome is comprised of approximately 1,100 proteins,¹ all but 12 of which are encoded by the nuclear genome in C. elegans. The expression of nuclear-encoded mitochondrial proteins varies widely across cell lineages and metabolic states,²^,³^,⁴ but the factors that specify these programs are not known. Here, we identify mutations in two nuclear-localized mRNA processing proteins, CMTR1/CMTR-1 and SRRT/ARS2/SRRT-1, which we show act via the same mechanism to rescue the mitochondrial complex I mutant NDUFS2/gas-1(fc21). CMTR-1 is an FtsJ-family RNA methyltransferase that, in mammals, 2'-O-methylates the first nucleotide 3' to the mRNA CAP to promote RNA stability and translation⁵^,⁶^,⁷^,⁸. The mutations isolated in cmtr-1 are dominant and lie exclusively in the regulatory G-patch domain. SRRT-1 is an RNA binding partner of the nuclear cap-binding complex and determines mRNA transcript fate.⁹ We show that cmtr-1 and srrt-1 mutations activate embryonic expression of NDUFS2/nduf-2.2, a paralog of NDUFS2/gas-1 normally expressed only in dopaminergic neurons, and that nduf-2.2 is necessary for the complex I rescue by the cmtr-1 G-patch mutant. Additionally, we find that loss of the cmtr-1 G-patch domain cause ectopic localization of CMTR-1 protein to processing bodies (P bodies), phase-separated organelles involved in mRNA storage and decay.¹⁰ P-body localization of the G-patch mutant CMTR-1 contributes to the rescue of the hyperoxia sensitivity of the NDUFS2/gas-1 mutant. This study suggests that mRNA methylation at P bodies may control nduf-2.2 gene expression, with broader implications for how the mitochondrial proteome is translationally remodeled in the face of tissue-specific metabolic requirements and stress.

01 Jul 2023·Cell Reports

Essential roles of RNA cap-proximal ribose methylation in mammalian embryonic development and fertility

Article

Author: Pillai, Ramesh S ; Homolka, David ; Li, Lingyun ; Fleury-Olela, Fabienne ; Vågbø, Cathrine Broberg ; Mendel, Mateusz ; Panasenko, Olesya ; Krasnykov, Kyrylo ; Dohnalkova, Michaela

Eukaryotic RNA pol II transcripts are capped at the 5' end by the methylated guanosine (m⁷G) moiety. In higher eukaryotes, CMTR1 and CMTR2 catalyze cap-proximal ribose methylations on the first (cap1) and second (cap2) nucleotides, respectively. These modifications mark RNAs as "self," blocking the activation of the innate immune response pathway. Here, we show that loss of mouse Cmtr1 or Cmtr2 leads to embryonic lethality, with non-overlapping sets of transcripts being misregulated, but without activation of the interferon pathway. In contrast, Cmtr1 mutant adult mouse livers exhibit chronic activation of the interferon pathway, with multiple interferon-stimulated genes being expressed. Conditional deletion of Cmtr1 in the germline leads to infertility, while global translation is unaffected in the Cmtr1 mutant mouse liver and human cells. Thus, mammalian cap1 and cap2 modifications have essential roles in gene regulation beyond their role in helping cellular transcripts to evade the innate immune system.

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CMTR1

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