Molecule Information

General Information of the Molecule (ID: Mol04384)

• 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

Lenalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KMS-11 cells; Pleural effusion; Homo sapiens (Human); CVCL_2989
• In Vivo Model: NSG female mice model; Mus musculus
• Experiment for Molecule Alteration: RNA sequencing assay; Whole-exome sequencing assay; qRT-PCR; Western blot assay; ELISA assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay; Cell cycle assay; Apoptosis assay
• Mechanism Description: Here, we identified adenosine deaminase acting on RNA1 (ADAR1) as a novel driver of lenalidomide resistance in MM. We showed that lenalidomide activates the MDA5-mediated double-stranded RNA (dsRNA)-sensing pathway in MM cells, leading to interferon (IFN)-mediated apoptosis, with ADAR1 as the key regulator. Mechanistically, ADAR1 loss increased lenalidomide sensitivity through endogenous dsRNA accumulation, which in turn triggered dsRNA-sensing pathways and enhanced IFN responses. Conversely, ADAR1 overexpression reduced lenalidomide sensitivity, attributed to increased RNA editing frequency, reduced dsRNA accumulation, and suppression of the dsRNA-sensing pathways. In summary, we report the involvement of ADAR1-regulated dsRNA sensing in modulating lenalidomide sensitivity in MM. These findings highlight a novel RNA-related mechanism underlying lenalidomide resistance and underscore the potential of targeting ADAR1 as a novel therapeutic strategy.

References

• Ref 1: The ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma. Blood. 2025 Mar 13;145(11):1164-1181.