IndraLab
Statements
sparser
"Considering that 1-200 aa is sufficient to directly interact with eIF3h ( xref and xref ) and that 1-200 aa can promote translation in tethering experiments whereas 1-150 aa does not ( xref ), we reasoned that a region between 150-200 aa must be important for the physical and functional METTL3-eIF3h interaction."
sparser
"Finally, upon knockdown of METTL3, endogenous BRD4 expression is strongly reduced, independently of mRNA abundance, leading to the discovery that METTL3-eIF3h mediates N 6 -methyladenosine (m 6 A) modification ( xref ) and circularization of BRD4 mRNA to enhance translation and promote oncogenesis ( xref ) ( xref )."
sparser
"This is supported by; 1) the position-dependent effects of METTL3 tethering on mRNA translation, 2) EM visualization of METTL3 bound to endogenous polyribosomes and its proximity to cap-binding proteins, 3) METTL3 interaction with eIF3h, and 4) Disruption of METTL3-eIF3h interaction abolishes the ability of METTL3 to promote translation, affect polysome conformation, or promote oncogenic transformation."
sparser
"It has been found that stem cells can be differentiated into malignant cells under unfavorable microenvironments. xref Although most of the current support for malignant tumors stems from the malignant transformation of stem cells, the mechanism of stem cell deterioration is still controversial. xref , xref For example, METTL3-eIF3h promotes stem cell deterioration, xref and farnesoid X receptor (FXR) regulates the proliferation of small-intestinal cancer stem cells (CSCs). xref , xref , xref C-Myc is related to the malignant differentiation of leukemia stem cells. xref Studies have found that JAK/STAT is highly activated in tumor stem cells. xref Studies have confirmed that liver CSCs are closely related to the recurrence of liver cancer. xref It is not clear what causes the accumulation of genetic errors of stem cells and changes in telomere function, which eventually evolve into malignant stem cells."
reach
"Interestingly, the oncogenic function of METTL3 in NSCLC is complicated, where METTL3 could methylate YAP mRNA and recruit YTHDF1/3 and eIF3b to promote translation of YAP mRNA, or could interact with eIF3h to promote translation of target mRNAs (e.g., BRD4) independent of its enzymatic activity."
sparser
"METTL3 promotes the translation of mRNA through different mechanisms: METTL3 interacts with eIF3h to promote the cyclization of mRNA, resulting in increased ribosomal efficiency and thus enhanced translation efficiency of target mRNA, independent of its catalytic activity ( xref )."
sparser
"Choe et al. showed that the METTL3-eIF3h complex enhances the translation of bromodomain containing 4 (BRD4), which is also modified by m 6 A in lung cancer cells when tethered to reporter mRNA at sites near the stop codon, supporting an mRNA looping mechanism for ribosome recycling and translational control ( xref , xref )."
sparser
"In mammals, a direct functional and physical interaction between METTL3 and eIF3h supports the mRNA looping mechanism for ribosome recycling and translational control [ xref ], since eIF3 is essential for the attachment of the recycled 40S subunits to mRNA to start a new round [ xref , xref ]."
sparser
"Compared with WT, the S118A mutant promoted the degradation of METTL3 (Fig. xref I), inhibited the binding of METTL3 and EIF3H (Fig. xref J), and the ubiquitination experiment also proved that the S118A mutation significantly enhanced the ubiquitination modification of METTL3 compared with WT (Fig. S xref L)."
sparser
"Further investigation revealed that dephosphorylation of METTL3 S2 disrupted the METTL3–eukaryotic translation initiation factor 3 subunit H (eIF3H) interaction, thereby suppressing the translation of oncogenes involved in replication stress responses, including bromine domain protein 4 ( BRD4 ) and serpin family E member 2 ( SERPINE2 ), ultimately enhancing sensitivity to OXA."
sparser
"Surprisingly, two groups of proteins not normally associated with replication stabilization were revealed by these screens, namely the olfactory receptor family, and a set of oncogenic proteins encoded by long mRNAs whose translation is controlled by the EIF3H-METTL3 master regulator."
sparser
"Network analysis of the twenty-nine hits common to the three non-B DNA cell lines showed that twenty-seven of the twenty-nine hits could be organized into a transcriptional (G0S2 [ xref , xref ], SUDS3 [ xref ]) or translational (EIF3H-METTL3 [ xref ]) regulatory hierarchy ( xref )."
sparser
"The twelve hits that overlapped and showed consistent enrichment across all treatments ( xref B) included COPS2, a subunit of the COP9 (CSN) signalosome that regulates DNA repair and translesion polymerase binding to PCNA through deneddylation of CRL4 CDT2 [ xref ]; G0S2, a tumor suppressor [ xref , xref ] and oncogene [ xref ] which blocks PIK3/mTOR signaling, oncogene-induced transformation and the anti-apoptotic function of the Bcl-2/Bax complex [ xref , xref , xref ]; SRSF8, which binds to the ATM (Ataxia Telangiectasia Mutated) kinase [ xref ]; SUDS3, a subunit of the Sin3/HDAC corepressor complex [ xref ]; and the translation regulator EIF3H, which binds to METTL3 to promote translation of a large subset of oncogenic mRNAs [ xref ]."
reach
"Research indicated that METTL3-eIF3h complex tethers to the m A modified stop codon of targeted mRNAs to promote their translation.37 YTHDF1 binds to m A-modified mRNAs to promote their translation by interacting with ribosomes and initiation factors, while YTHDF2 promotes mRNA decay.38 Interestingly, YTHDF3 enhances or suppresses mRNA translation depending on binding to YTHDF1 or YTHDF2."
sparser
"Therefore, we hypothesized that METTL3 S2 phosphorylation may influence its binding to eIF3H. To validate this, we performed CoIP and found that the binding of METTL3 S2A to eIF3H was notably weaker than that of METTL3 WT, indicating that dephosphorylation of METTL3 S2 weakens its interaction with eIF3H ( xref , and fig."
sparser
"In eukaryotic cells, initiation efficiency is considered the rate‐limiting step of translation xref ] and studies have reported that many m 6 A regulatory factors facilitate translation by interacting with translation initiation factors. [ xref ] METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon, and the METTL3‐eIF3h interaction is required for enhanced translation, the formation of densely packed polyribosomes and oncogenic transformation. [ xref ] METTL16 promotes the translation of thousands of mRNA transcripts in the cytosol via the recruitment of eIF3a/b and ribosomal RNAs to facilitate the formation of the 40S preinitiation complex and 80S translation‐initiation complex. [ xref ] YTHDF1 can bind to m 6 A‐modified mRNA of eIF3c, consequently enhancing translation. [ xref ] In addition, eIF2AK2 bridges YTHDF3 and eIF3a, enhancing the stability of the YTHDF3/eIF3a complex to facilitate the translation of target genes. [ xref ] Under heat shock stress conditions, YTHDF2 translocates to the nucleus to protect m 6 A motifs in the 5′UTR of stress‐induced transcripts and activates cap‐independent translation initiation. [ xref ] Here, we reported that the role of YTHDF2 in promoting the translation of m 6 A‐motified ETV5 mRNA relies on eIF3b, the main scaffolding subunit in the eIF3 complex, [ xref ] and the W278 site of YTHDF2 directly binds to and recruits eIF3b to ETV5 mRNA."
sparser
"Research indicated that METTL3-eIF3h complex tethers to the m 6 A modified stop codon of targeted mRNAs to promote their translation. xref YTHDF1 binds to m 6 A-modified mRNAs to promote their translation by interacting with ribosomes and initiation factors, while YTHDF2 promotes mRNA decay. xref Interestingly, YTHDF3 enhances or suppresses mRNA translation depending on binding to YTHDF1 or YTHDF2. xref In liver cancer, YTHDF2 increases the m 6 A level in the 5′UTR of OCT4 mRNA leading to enhanced protein translation of OCT4, and mutation in the corresponding m 6 A modification site decreases OCT4 expression. xref Moreover, Li et al also reported that YTHDF3 promotes the translation of its targets by combining with YTHDF1. xref "
sparser
"On the other hand, new evidence of functional mRNA cyclization came from recent studies of m 6 A mRNA methylation that brings 5′ and 3′ UTRs together via eIF3h–METTL3 interaction and/or cap/eIF4F/eIF3/YTHDF1/m6A bridge formation, which facilitates translation during oncogenesis [ xref , xref ]."
sparser
"Previous studies showed that besides the YTHDF1-eIF3 looping model, m 6 A modifications localized to 5′UTRs can recruit eIF3 directly to induce translation, independent of eIF4E cap binding xref ; the m 6 A sites close to the stop codon can also form an mRNA loop through the interaction between METTL3 and eIF3h, enhancing mRNA translation xref ."
reach
"Choe et al. showed that the METTL3-eIF3h complex enhances the translation of bromodomain containing 4 (BRD4), which is also modified by m A in lung cancer cells when tethered to reporter mRNA at sites near the stop codon, supporting an mRNA looping mechanism for ribosome recycling and translational control (33, 69)."
reach
"This is supported by; 1) the position dependent effects of METTL3 tethering on mRNA translation, 2) EM visualization of METTL3 bound to endogenous polyribosomes and its proximity to cap binding proteins, 3) METTL3 interaction with eIF3h, and 4) Disruption of METTL3-eIF3h interaction abolishes the ability of METTL3 to promote translation, affect polysome conformation, or promote oncogenic transformation."