Molecule Information

General Information of the Molecule (ID: Mol04385)

• Name: Double-stranded RNA-specific adenosine deaminase (ADAR) ,Homo sapiens
• Synonyms: 136 kDa double-stranded RNA-binding protein; Interferon-inducible protein 4; K88DSRBP
• Molecule Type: Protein
• Gene Name: ADAR
• Gene ID: 103
• Sequence:
  MNPRQGYSLSGYYTHPFQGYEHRQLRYQQPGPGSSPSSFLLKQIEFLKGQLPEAPVIGKQ
  TPSLPPSLPGLRPRFPVLLASSTRGRQVDIRGVPRGVHLRSQGLQRGFQHPSPRGRSLP
  Q RGVDCLSSHFQELSIYQDQEQRILKFLEELGEGKATTAHDLSGKLGTPKKEINRVLYS
  LA KKGKLQKEAGTPPLWKIAVSTQAWNQHSGVVRPDGHSQGAPNSDPSLEPEDRNSTSV
  SED LLEPFIAVSAQAWNQHSGVVRPDSHSQGSPNSDPGLEPEDSNSTSALEDPLEFLDM
  AEIK EKICDYLFNVSDSSALNLAKNIGLTKARDINAVLIDMERQGDVYRQGTTPPIWHL
  TDKKR ERMQIKRNTNSVPETAPAAIPETKRNAEFLTCNIPTSNASNNMVTTEKVENGQE
  PVIKLE NRQEARPEPARLKPPVHYNGPSKAGYVDFENGQWATDDIPDDLNSIRAAPGEF
  RAIMEMP SFYSHGLPRCSPYKKLTECQLKNPISGLLEYAQFASQTCEFNMIEQSGPPHE
  PRFKFQVV INGREFPPAEAGSKKVAKQDAAMKAMTILLEEAKAKDSGKSEESSHYSTEK
  ESEKTAESQ TPTPSATSFFSGKSPVTTLLECMHKLGNSCEFRLLSKEGPAHEPKFQYCV
  AVGAQTFPSV SAPSKKVAKQMAAEEAMKALHGEATNSMASDNQPEGMISESLDNLESMM
  PNKVRKIGELV RYLNTNPVGGLLEYARSHGFAAEFKLVDQSGPPHEPKFVYQAKVGGRW
  FPAVCAHSKKQG KQEAADAALRVLIGENEKAERMGFTEVTPVTGASLRRTMLLLSRSPE
  AQPKTLPLTGSTF HDQIAMLSHRCFNTLTNSFQPSLLGRKILAAIIMKKDSEDMGVVVS
  LGTGNRCVKGDSLS LKGETVNDCHAEIISRRGFIRFLYSELMKYNSQTAKDSIFEPAKG
  GEKLQIKKTVSFHLY ISTAPCGDGALFDKSCSDRAMESTESRHYPVFENPKQGKLRTKV
  ENGEGTIPVESSDIVP TWDGIRLGERLRTMSCSDKILRWNVLGLQGALLTHFLQPIYLK
  SVTLGYLFSQGHLTRAI CCRVTRDGSAFEDGLRHPFIVNHPKVGRVSIYDSKRQSGKTK
  ETSVNWCLADGYDLEILD GTRGTVDGPRNELSRVSKKNIFLLFKKLCSFRYRRDLLRLS
  YGEAKKAARDYETAKNYFK KGLKDMGYGNWISKPQEEKNFYLCPV
• Function: Catalyzes the hydrolytic deamination of adenosine to inosinein double-stranded RNA referred to as A-to-I RNA editing. This may affect geneexpression and function in a number of ways that include mRNAtranslation by changing codons and hence the amino acid sequence ofproteins since the translational machinery read the inosine as aguanosine; pre-mRNA splicing by altering splice site recognitionsequences; RNA stability by changing sequences involved in nucleaserecognition; genetic stability in the case of RNA virus genomes bychanging sequences during viral RNA replication; and RNA structure-dependent activities such as microRNA production or targeting orprotein-RNA interactions. Can edit both viral and cellular RNAs and canedit RNAs at multiple sites or at specific sites . Its cellular RNA substrates include: bladder cancer-associated protein , neurotransmitter receptors for glutamate and serotonin and GABA receptor . Site-specificRNA editing of transcripts encoding these proteins results in aminoacid substitutions which consequently alters their functionalactivities. Exhibits low-level editing at the GRIA2 Q/R site, but editsefficiently at the R/G site and HOTSPOT1. Its viral RNA substratesinclude: hepatitis C virus , vesicular stomatitis virus ,measles virus , hepatitis delta virus , and humanimmunodeficiency virus type 1 . Exhibits either a proviral or an antiviral effect and this can beediting-dependent , editing-independent orboth . Impairs HCV replication via RNA editing at multiplesites. Enhances the replication of MV, VSV and HIV-1 through anediting-independent mechanism via suppression of EIF2AK2/PKR activationand function. Stimulates both the release and infectivity of HIV-1viral particles by an editing-dependent mechanism where it associateswith viral RNAs and edits adenosines in the 5'UTR and the Rev and Tatcoding sequence. Can enhance viral replication of HDV via A-to-Iediting at a site designated as amber/W, thereby changing an UAG amberstop codon to an UIG tryptophan codon that permits synthesis of thelarge delta antigen which has a key role in the assembly ofviral particles. However, high levels of ADAR1 inhibit HDV replication.{ECO:0000269|PubMed:12618436, ECO:0000269|PubMed:15556947,ECO:0000269|PubMed:15858013, ECO:0000269|PubMed:16120648,ECO:0000269|PubMed:16475990, ECO:0000269|PubMed:17079286,ECO:0000269|PubMed:19605474, ECO:0000269|PubMed:19651874,ECO:0000269|PubMed:19710021, ECO:0000269|PubMed:19908260,ECO:0000269|PubMed:21289159, ECO:0000269|PubMed:22278222,ECO:0000269|PubMed:7565688, ECO:0000269|PubMed:7972084}.
• Uniprot ID: DSRAD_HUMAN
• Ensembl ID: ENSG0000016071019
• HGNC ID: HGNC:225

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

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

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

Lenvatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [1]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Missense mutation; Loss
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: B76.1/Huh7 cells; N.A.; Homo sapiens (Human); CVCL_U443
• In Vitro Model: MHCC97H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: NYG male nude mice model; Balb/c male nude mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; RNA extraction assay; RT-PCR; RNA sequencing assay; ChIP-qPCR; Immunohistochemistry
• Experiment for Drug Resistance: Viability assay
• Mechanism Description: Key results: Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo.Conclusion and implications: AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.

References

• Ref 1: Loss of AXIN1 regulates response to lenvatinib through a WNT/KDM5B/p15 signalling axis in hepatocellular carcinoma. Br J Pharmacol. 2025 Mar;182(6):1394-1409.