Molecule Information

General Information of the Molecule (ID: Mol04130)

• Name: Methyltransferase like 3 (METTL3) ,Homo sapiens
• Synonyms: Methyltransferase-like protein 3; N(6)-adenosine-methyltransferase 70 kDa subunit
• Molecule Type: Protein
• Gene Name: METTL3
• Gene ID: 56339
• Location: chr14:21498133-21511342[-]
• Sequence:
  MSDTWSSIQAHKKQLDSLRERLQRRRKQDSGHLDLRNPEAALSPTFRSDSPVPTAPTSGG
  PKPSTASAVPELATDPELEKKLLHHLSDLALTLPTDAVSICLAISTPDAPATQDGVESLL
  QKFAAQELIEVKRGLLQDDAHPTLVTYADHSKLSAMMGAVAEKKGPGEVAGTVTGQKRRA
  EQDSTTVAAFASSLVSGLNSSASEPAKEPAKKSRKHAASDVDLEIESLLNQQSTKEQQSK
  KVSQEILELLNTTTAKEQSIVEKFRSRGRAQVQEFCDYGTKEECMKASDADRPCRKLHFR
  RIINKHTDESLGDCSFLNTCFHMDTCKYVHYEIDACMDSEAPGSKDHTPSQELALTQSVG
  GDSSADRLFPPQWICCDIRYLDVSILGKFAVVMADPPWDIHMELPYGTLTDDEMRRLNIP
  VLQDDGFLFLWVTGRAMELGRECLNLWGYERVDEIIWVKTNQLQRIIRTGRTGHWLNHGK
  EHCLVGVKGNPQGFNQGLDCDVIVAEVRSTSHKPDEIYGMIERLSPGTRKIELFGRPHNV
  QPNWITLGNQLDGIHLLDPDVVARFKQRYPDGIISKPKNL
• 3D-structure: PDB ID: 5TEY; Classification: Transferase; Method: X-ray diffraction; Resolution: 1.80 Å
• Function: The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some RNAs and regulates various processes such as the circadian clock, differentiation of embryonic and hematopoietic stem cells, cortical neurogenesis, response to DNA damage, differentiation of T-cells and primary miRNA processing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:27281194, PubMed:27373337, PubMed:27627798, PubMed:28297716, PubMed:29348140, PubMed:29506078, PubMed:30428350, PubMed:9409616). In the heterodimer formed with METTL14, METTL3 constitutes the catalytic core (PubMed:27281194, PubMed:27373337, PubMed:27627798). N6- methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability, processing, translation efficiency and editing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:28297716, PubMed:9409616). M6A acts as a key regulator of mRNA stability: methylation is completed upon the release of mRNA into the nucleoplasm and promotes mRNA destabilization and degradation (PubMed:28637692). In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A regulates the length of the circadian clock: acts as an early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also regulates circadian regulation of hepatic lipid metabolism (PubMed:30428350). M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis (By similarity). Also required for oogenesis (By similarity). Involved in the response to DNA damage: in response to ultraviolet irradiation, METTL3 rapidly catalyzes the formation of m6A on poly(A) transcripts at DNA damage sites, leading to the recruitment of POLK to DNA damage sites (PubMed:28297716). M6A is also required for T-cell homeostasis and differentiation: m6A methylation of transcripts of SOCS family members (SOCS1, SOCS3 and CISH) in naive T-cells promotes mRNA destabilization and degradation, promoting T-cell differentiation (By similarity). Inhibits the type I interferon response by mediating m6A methylation of IFNB (PubMed:30559377). M6A also takes place in other RNA molecules, such as primary miRNA (pri- miRNAs) (PubMed:25799998). Mediates m6A methylation of Xist RNA, thereby participating in random X inactivation: m6A methylation of Xist leads to target YTHDC1 reader on Xist and promote transcription repression activity of Xist (PubMed:27602518). M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells (By similarity). METTL3 mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998). Acts as a positive regulator of mRNA translation independently of the methyltransferase activity: promotes translation by interacting with the translation initiation machinery in the cytoplasm (PubMed:27117702). Its overexpression in a number of cancer cells suggests that it may participate in cancer cell proliferation by promoting mRNA translation (PubMed:27117702). During human coronavirus SARS-CoV-2 infection, adds m6A modifications in SARS-CoV-2 RNA leading to decreased RIGI binding and subsequently dampening the sensing and activation of innate immune responses (PubMed:33961823). .
• Uniprot ID: MTA70_HUMAN
• Ensembl ID: ENSG00000165819
• HGNC ID: HGNC:17563

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW-480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1alpha), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells.

Tretinoin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Acute promyelocytic leukemia [ICD-11: 2A60.2] [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Tretinoin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: NB4 cells transfected with METTL3-OE were transplanted into BALB/C nude mice via subcutaneously inoculation; NB4 cells transfected with METTL3-OE were transplanted into BALB/C nude mice via tail vein injection; Mice
• Experiment for Molecule Alteration: Western blot analysis, qRT-PCR and CO-IP
• Experiment for Drug Resistance: Tumor images assay; Tumor volume assay; Tumor weight assay
• Mechanism Description: Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3.

References

• Ref 1: N(6)-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming. Theranostics. 2022 Jun 13;12(10):4802-4817.
• Ref 2: 20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3. J Ginseng Res. 2024 May;48(3):298-309.