Molecule Information

General Information of the Molecule (ID: Mol04446)

• Name: YTH domain-containing family protein 2 ,Homo sapiens
• Synonyms: CLL-associated antigen KW-14 ; High-glucose-regulated protein 8 ; Renal carcinoma antigen NY-REN-2
• Molecule Type: Protein
• Gene ID: 51441
• Sequence:
  MSASSLLEQRPKGQGNKVQNGSVHQKDGLNDDDFEPYLSPQARPNNAYTAMSDSYLPSYY
  SPSIGFSYSLGEAAWSTGGDTAMPYLTSYGQLSNGEPHFLPDAMFGQPGALGSTPFLGQ
  H GFNFFPSGIDFSAWGNNSSQGQSTQSSGYSSNYAYAPSSLGGAMIDGQSAFANETLNK
  AP GMNTIDQGMAALKLGSTEVASNVPKVVGSAVGSGSITSNIVASNSLPPATIAPPKPA
  SWA DIASKPAKQQPKLKTKNGIAGSSLPPPPIKHNMDIGTWDNKGPVAKAPSQALVQNI
  GQPT QGSPQPVGQQANNSPPVAQASVGQQTQPLPPPPPQPAQLSVQQQAAQPTRWVAPR
  NRGSG FGHNGVDGNGVGQSQAGSGSTPSEPHPVLEKLRSINNYNPKDFDWNLKHGRVFI
  IKSYSE DDIHRSIKYNIWCSTEHGNKRLDAAYRSMNGKGPVYLLFSVNGSGHFCGVAEM
  KSAVDYN TCAGVWSQDKWKGRFDVRWIFVKDVPNSQLRHIRLENNENKPVTNSRDTQEV
  PLEKAKQV LKIIASYKHTTSIFDDFSHYEKRQEEEESVKKERQGRGK
• Function: Specifically recognizes and binds N6-methyladenosine -containing RNAs, and regulates their stability . M6A is amodification present at internal sites of mRNAs and some non-codingRNAs and plays a role in mRNA stability and processing. Acts as a regulator of mRNA stability by promotingdegradation of m6A-containing mRNAs via interaction with the CCR4-NOTand ribonuclease P/MRP complexes, depending on the context. The YTHDF paralogs sharem6A-containing mRNAs targets and act redundantly to mediate mRNAdegradation and cellular differentiation . M6A-containing mRNAs containing a binding site forRIDA/HRSP12 are preferentially degraded byendoribonucleolytic cleavage: cooperative binding of RIDA/HRSP12 andYTHDF2 to transcripts leads to recruitment of the ribonuclease P/MRPcomplex . Other m6A-containing mRNAs undergodeadenylation via direct interaction between YTHDF2 and CNOT1, leadingto recruitment of the CCR4-NOT and subsequent deadenylation of m6A-containing mRNAs . Required maternally to regulateoocyte maturation: probably acts by binding to m6A-containing mRNAs,thereby regulating maternal transcript dosage during oocyte maturation,which is essential for the competence of oocytes to sustain earlyzygotic development . Also required duringspermatogenesis: regulates spermagonial adhesion by promotingdegradation of m6A-containing transcripts coding for matrixmetallopeptidases . Also involved in hematopoietic stemcells specification by binding to m6A-containing mRNAs, leading topromote their degradation . Also acts as a regulatorof neural development by promoting m6A-dependent degradation of neuraldevelopment-related mRNA targets . Inhibits neuralspecification of induced pluripotent stem cells by binding tomethylated neural-specific mRNAs and promoting their degradation,thereby restraining neural differentiation . Regulatescircadian regulation of hepatic lipid metabolism: acts by promotingm6A-dependent degradation of PPARA transcripts .Regulates the innate immune response to infection by inhibiting thetype I interferon response: acts by binding to m6A-containing IFNBtranscripts and promoting their degradation . May alsoact as a promoter of cap-independent mRNA translation following heatshock stress: upon stress, relocalizes to the nucleus and specificallybinds mRNAs with some m6A methylation mark at their 5'-UTR, protectingdemethylation of mRNAs by FTO, thereby promoting cap-independent mRNAtranslation . Regulates mitotic entry by promoting thephase-specific m6A-dependent degradation of WEE1 transcripts. Promotes formation of phase-separated membranelesscompartments, such as P-bodies or stress granules, by undergoingliquid-liquid phase separation upon binding to mRNAs containingmultiple m6A-modified residues: polymethylated mRNAs act as amultivalent scaffold for the binding of YTHDF proteins, juxtaposingtheir disordered regions and thereby leading to phase separation.The resulting mRNA-YTHDF complexes then partition into differentendogenous phase-separated membraneless compartments, such as P-bodies,stress granules or neuronal RNA granules . May alsorecognize and bind RNAs modified by C5-methylcytosine and act asa regulator of rRNA processing .{ECO:0000250|UniProtKB:Q91YT7, ECO:0000269|PubMed:22575960,ECO:0000269|PubMed:24284625, ECO:0000269|PubMed:25412658,ECO:0000269|PubMed:25412661, ECO:0000269|PubMed:26046440,ECO:0000269|PubMed:26318451, ECO:0000269|PubMed:26458103,ECO:0000269|PubMed:27558897, ECO:0000269|PubMed:28106072,ECO:0000269|PubMed:30065315, ECO:0000269|PubMed:30428350,ECO:0000269|PubMed:30559377, ECO:0000269|PubMed:30930054,ECO:0000269|PubMed:31292544, ECO:0000269|PubMed:31388144,ECO:0000269|PubMed:31642031, ECO:0000269|PubMed:31815440,ECO:0000269|PubMed:32169943, ECO:0000269|PubMed:32267835,ECO:0000269|PubMed:32451507, ECO:0000269|PubMed:32492408}.; Promotes viral gene expression andreplication of polyomavirus SV40: acts by binding to N6-methyladenosine-containing viral RNAs .{ECO:0000269|PubMed:29447282}.; Promotes viral gene expression andvirion production of kaposis sarcoma-associated herpesvirus atsome stage of the KSHV life cycle . Acts by binding to N6-methyladenosine -containing viral RNAs . {ECO:0000269|PubMed:29659627}.
• Uniprot ID: YTHD2_HUMAN
• Ensembl ID: ENSG0000019849216
• HGNC ID: HGNC:31675

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

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Cervical cancer [ICD-11: 2C77.0] [1]

• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Down-regulation
• Mechanism Description: We discovered FGD5-AS1 and the RNA methylation reader protein, YTHDF2, were positively associated with 5-Fu resistance in cervical cancer. A positive correlation between FGD5-AS1 and YTHDF2 was found in cervical tumor tissues. Expressions of FGD5-AS1 and YTHDF2 were significantly upregulated in the established 5-Fu resistant cervical cancer cells. MiRNA-microArray analysis screened that FGD5-AS1 downregulated miR-130a-3p expression in cervical cancer cells. Subsequently, we demonstrated FGD5-AS1 acted as a ceRNA by sponging miR-130a-3p, which targeted the 3'UTR of YTHDF2 mRNA. Rescue experiments validated overexpression of FGD5-AS1 increased 5-Fu resistance in cervical cancer cells, which was reversed by miR-130a-3p overexpression. Finally, combining FGD5-AS1 silencing with 5-Fu treatments resulted in a synergistic inhibitory effect (CI < 1) on the viability of cervical cancer cells. This study reveals a FGD5-AS1-miR-130a-3p-YTHDF2 axis that could be a promising therapeutic target for overcoming 5-Fu resistance in cervical cancer.

References

• Ref 1: LncRNA-FGD5-AS1 promotes 5-Fu resistance of cervical cancer cells through modulating the miR-130a-3p-YTHDF2 axis. J Chemother. 2024 Dec 6:1-13.