Affinage

RAI1

Retinoic acid-induced protein 1 · UniProt Q7Z5J4

Length
1906 aa
Mass
203.4 kDa
Annotated
2026-06-10
98 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAI1 is a dosage-sensitive nuclear transcriptional regulator that controls programs for neural circuit assembly, circadian timing, and metabolic homeostasis (PMID:27693255, PMID:17024248). In vertebrate cells it localizes to the nucleus and activates transcription through a transactivation domain that is structurally separable from its nuclear localization signal, such that N-terminal truncations cause cytoplasmic mislocalization while C-terminal mutations preserve nuclear import but abolish transactivation (PMID:23028815, PMID:20738874). Genome-wide, RAI1 preferentially occupies DNA near active promoters and drives expression of genes governing neuronal communication, and its dynamic chromatin occupancy couples to activity-dependent nascent transcription and synaptic scaling (PMID:27693255, PMID:32783930). Direct target genes include the circadian regulator CLOCK, whose downregulation upon RAI1 haploinsufficiency propagates to PER2, PER3, CRY1, and BMAL1 (PMID:22578325), and the neurotrophin BDNF, which RAI1 activates via an enhancer; restoring BDNF reverses the obesity, hyperphagia, and hyposociability of Rai1-deficient mice, placing RAI1 genetically upstream of BDNF in hypothalamic body-weight control (PMID:20663924, PMID:34463714, PMID:37956053). At the circuit level RAI1 acts in defined neuron types — loss in glutamatergic neurons raises dentate gyrus excitability and seizure susceptibility, while loss in Sim1+/SF1+ hypothalamic cells causes obesity (PMID:27693255, PMID:36256819). RAI1 protein abundance is set post-translationally: TRIM27 binds RAI1 and directs K48/K63-linked ubiquitination and proteasomal degradation (PMID:42140622), and RAI1 assembles into a chromatin-associated complex with TCF20, PHF14, and HMG20A (PMID:38289192). Rai1 dosage alone accounts for the dup(17)(p11.2) syndrome phenotypes (PMID:17024248), and timed normalization of Rai1 in juvenile mice corrects developmental gene expression and reverses social deficits (PMID:30275311). The deeply conserved fungal Rai1 ortholog is additionally a multifunctional RNA 5'-end processing enzyme — a single divalent-cation active site supports pyrophosphohydrolase, deFADding, deCoAping, and 5'-hydroxyl dinucleotide hydrolase activities — and it binds and stimulates the Rat1/XRN2 5'→3' exoribonuclease within the RNA polymerase II transcription-termination torpedo complex, recruited via Rtt103 (PMID:19194460, PMID:10805743, PMID:26101253, PMID:32374864, PMID:31777937, PMID:40188244).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2000 High

    Established the ancestral biochemical role of the Rai1 family by showing the yeast ortholog binds and stimulates the nuclear 5'→3' exoribonuclease Rat1, placing it in RNA processing/ribosome biogenesis.

    Evidence in vitro exoribonuclease assays plus genetic epistasis (RAT1 overexpression rescue, synthetic lethality) in S. cerevisiae

    PMID:10805743

    Open questions at the time
    • Did not resolve the structural basis of Rat1 stimulation
    • Did not identify intrinsic catalytic activity of Rai1 itself
  2. 2005 High

    Reframed mammalian RAI1 as a nuclear transcription factor and a developmentally essential, dosage-sensitive gene rather than only an RNA-processing factor.

    Evidence GFP/GAL4-fusion transactivation assays, lacZ expression mapping, and mouse haploinsufficiency phenotyping

    PMID:15746153

    Open questions at the time
    • No DNA-binding specificity or direct target genes identified
    • Transactivation domain not yet mapped
  3. 2006 High

    Demonstrated that Rai1 dosage alone is the causal driver of dup(17)(p11.2) syndrome, isolating it as the single dosage-sensitive gene in the interval.

    Evidence genetic epistasis in compound heterozygous duplication + Rai1-null mice with behavioral and body-weight readouts

    PMID:17024248

    Open questions at the time
    • Molecular targets mediating dosage sensitivity not defined
    • Does not address which cell types are responsible
  4. 2009 High

    Provided the structural mechanism for Rat1 activation and revealed that Rai1 itself is a pyrophosphohydrolase acting on 5'-triphosphorylated RNA via a conserved cation-coordinating pocket.

    Evidence 2.2 Å crystal structure of the S. pombe Rat1–Rai1 complex with in vitro assays and active-site mutagenesis

    PMID:19194460

    Open questions at the time
    • Did not establish whether mammalian RAI1 retains catalytic activity
    • Physiological RNA substrates in vivo not defined
  5. 2010 High

    Identified BDNF as a direct transcriptional target of RAI1 and linked this to the hyperphagia/obesity phenotype, and localized transactivation to separable protein regions.

    Evidence BDNF enhancer luciferase reporter assays, hypothalamic qRT-PCR, immunofluorescence, and obesity phenotyping in mice

    PMID:20663924 PMID:20738874

    Open questions at the time
    • Direct RAI1 binding to the BDNF enhancer not shown by ChIP
    • DNA-recognition mechanism unresolved
  6. 2012 High

    Connected RAI1 to circadian control by establishing CLOCK as a direct target and showing downstream oscillator genes collapse upon haploinsufficiency.

    Evidence CLOCK promoter luciferase assays and qRT-PCR in SMS patient fibroblasts and mouse hypothalamus

    PMID:22578325

    Open questions at the time
    • Co-factors mediating CLOCK activation unknown
    • How circadian and metabolic target programs intersect not defined
  7. 2012 High

    Mapped functional architecture by showing the nuclear localization signal and transactivation domain reside in physically separable regions, explaining genotype–phenotype patterns of patient mutations.

    Evidence immunofluorescence, subcellular fractionation, and reporter assays in patient-derived cells and engineered constructs

    PMID:23028815

    Open questions at the time
    • Atomic structure of mammalian RAI1 domains not solved
    • Identity of the DNA/chromatin-binding determinant not yet defined
  8. 2013 Medium

    Proposed RAI1 as a chromatin/histone-code reader by identifying conserved ePHD/ADD, AT-hook, and nucleosome-binding modules that bind nucleosomes and histones.

    Evidence in vitro nucleosome/histone pulldowns, yeast two-hybrid, and phylogenetic domain analysis

    PMID:24205348

    Open questions at the time
    • No atomic-resolution structure of the binding modules
    • Specific histone marks recognized not established
    • Single-lab biochemistry without in vivo validation
  9. 2014 Medium

    Confirmed in a vertebrate embryo that Rai1 is required for neural crest, craniofacial, and forebrain development with reduced bdnf, generalizing the mouse findings.

    Evidence antisense morpholino knockdown in Xenopus with in situ hybridization, immunostaining, and TUNEL

    PMID:24878353

    Open questions at the time
    • Morpholino off-target effects not excluded by genetic rescue
    • Direct vs indirect regulation of bdnf not resolved
  10. 2016 High

    Defined RAI1's genome-wide regulatory logic and cell-type-specific functions, showing it occupies active promoters and drives neuronal communication genes with distinct deficits per neuron class.

    Evidence Rai1 ChIP-seq plus a panel of neuron-type-specific conditional knockouts with behavior and electrophysiology

    PMID:27693255

    Open questions at the time
    • Sequence motif/cofactors directing promoter occupancy not defined
    • Whether occupancy requires direct DNA binding vs chromatin tethering unclear
  11. 2018 High

    Established a postnatal therapeutic window by showing timed Rai1 restoration corrects developmental gene expression and reverses social deficits, and linked RAI1 to mPFC circuitry.

    Evidence inducible Rai1 reactivation mice, RNA-seq, Golgi spine analysis, and optogenetic mPFC activation

    PMID:30275311

    Open questions at the time
    • Molecular basis of the closing window unknown
    • Direct targets driving social behavior not isolated
  12. 2020 High

    Linked RAI1 chromatin dynamics to activity-dependent transcription and homeostatic synaptic scaling, defining a real-time transcriptional role in neurons.

    Evidence nascent RNA-seq (EU-seq), RAI1 ChIP-seq, and mEPSC electrophysiology in Rai1-knockout primary neurons

    PMID:32783930

    Open questions at the time
    • Signal pathways redirecting RAI1 occupancy with activity not defined
    • Causal target genes for scaling not pinpointed
  13. 2020 High

    Expanded the catalytic repertoire of the DXO/Rai1 family to non-canonical cap removal (deFADding, deCoAping) and 5'-OH dinucleotide hydrolysis, with structures and cellular validation.

    Evidence X-ray structures of DXO/Rai1 with FAD, CoA, and 5'-OH substrate mimics, in vitro decapping/nuclease assays, and FAD-capQ in human cells

    PMID:31777937 PMID:32374864

    Open questions at the time
    • Whether human RAI1 (vs DXO) performs these reactions in vivo not addressed
    • Biological RNA substrates in neurons unknown
  14. 2021 High

    Placed RAI1 genetically upstream of BDNF in hypothalamic body-weight regulation by showing BDNF overexpression rescues SMS-like metabolic and social phenotypes.

    Evidence inducible conditional Rai1 knockout with Bdnf-overexpression genetic rescue and metabolic phenotyping

    PMID:34463714

    Open questions at the time
    • Direct enhancer occupancy in vivo not shown
    • Other metabolic targets contributing not excluded
  15. 2022 High

    Attributed seizure susceptibility to glutamatergic Rai1 loss, identifying RAI1 as a negative regulator of dentate gyrus granule cell excitability.

    Evidence cell-type-specific knockouts, in vivo EEG/seizure challenge, patch-clamp, and c-Fos brain mapping

    PMID:36256819

    Open questions at the time
    • Transcriptional targets controlling intrinsic excitability not identified
    • Mechanism of synaptic vs intrinsic contribution not separated
  16. 2023 Medium

    Defined the native protein context of RAI1, showing it assembles into a TCF20-PHF14-HMG20A complex and associates with KMT2A subcomplexes, with TCF20 controlling RAI1 abundance.

    Evidence co-IP/mass spectrometry from marmoset brain, reciprocal co-IP in cancer stem cells, and abundance assays in human cells

    PMID:37709746 PMID:38289192

    Open questions at the time
    • Stoichiometry and structure of the complex unknown
    • Mechanism by which TCF20 controls RAI1 levels undefined
    • RAI1-specific contribution to KMT2A complex function not dissected
  17. 2023 High

    Provided a hypothalamic-circuit and pharmacological handle by mapping RAI1 to PVH BDNF-neuron excitability and showing a TrkB agonist mitigates SMS phenotypes.

    Evidence BDNF-Cre × Rai1-flox knockouts, PVH neuron electrophysiology, and LM22A-4 treatment with metabolic phenotyping

    PMID:37956053

    Open questions at the time
    • Whether TrkB agonism acts purely downstream of RAI1 not fully isolated
    • Long-term efficacy not established
  18. 2024 Medium

    Identified upstream cis-regulation of RAI1, showing an allele-specific enhancer SNP loops to the RAI1 promoter and recruits RXRα/RARα.

    Evidence luciferase reporters, RXRα/RARα ChIP, and 3C chromatin looping in human cell lines including SH-SY5Y

    PMID:38674394

    Open questions at the time
    • In vivo relevance of the SNP to phenotype not shown
    • Single-lab cell-line data
  19. 2024 High

    Refined the torpedo termination complex structure across species, showing conserved core folds but divergent Rtt103–Rai1 interfaces.

    Evidence cryo-EM and X-ray structures of Xrn2/Rat1–Rai1–Rtt103 complexes from two organisms

    PMID:39657659

    Open questions at the time
    • Functional consequence of interface variability not tested
    • Mammalian RAI1 role in this complex not addressed
  20. 2025 High

    Defined the recruitment mechanism, showing a short Rtt103 segment (Pro261/Tyr263) contacts Rai1 to tether Rat1-Rai1 to RNA Pol II for termination.

    Evidence 2.9 Å cryo-EM of the Rat1–Rai1–Rtt103 ternary complex with P261G/Y263A mutagenesis and co-purification

    PMID:40188244

    Open questions at the time
    • Whether mammalian RAI1 participates in analogous Pol II termination not shown
    • Coupling to nascent transcript handoff not resolved
  21. 2026 High

    Established post-translational control of RAI1 abundance, identifying TRIM27 as an E3-pathway destabilizer whose knockdown rescues SMS neuronal phenotypes.

    Evidence forward CRISPR screen, TRIM27-RAI1 co-IP, K48/K63 ubiquitination and proteasome assays, and shRNA rescue in primary neurons

    PMID:42140622

    Open questions at the time
    • Whether TRIM27 directly transfers ubiquitin to RAI1 vs via adaptors not fully resolved
    • Signals regulating TRIM27-RAI1 activity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether human RAI1 retains the ancestral RNA 5'-end processing/torpedo-termination enzymatic activities in addition to its transcription-factor role, and how its chromatin-reader modules direct genome-wide promoter occupancy, remain unresolved.
  • No demonstration of catalytic activity for mammalian RAI1
  • No defined DNA-recognition motif
  • Integration of RNA-processing and transcription roles untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 2 GO:0016787 hydrolase activity 2 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-112316 Neuronal System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 1 R-HSA-9909396 Circadian clock 1
Partners
HMG20AKMT2APHF14RAT1/XRN2RTT103TCF20TRIM27
Complex memberships
RAI1-TCF20-PHF14-HMG20A complexRat1(XRN2)-Rai1-Rtt103 torpedo termination complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Crystal structure of S. pombe Rat1 in complex with Rai1 at 2.2 Å resolution revealed the molecular mechanism for activation of Rat1 exoribonuclease by Rai1, and demonstrated that Rai1 possesses pyrophosphohydrolase activity toward 5' triphosphorylated RNA — the first demonstration of this activity in eukaryotes. Mutagenesis confirmed three conserved acidic residues in a large pocket of Rai1 coordinate a divalent cation required for this activity. Rai1 also enables Rat1 to degrade RNAs with stable secondary structure more effectively. X-ray crystallography (2.2 Å), in vitro biochemical assays, active-site mutagenesis Nature High 19194460
2000 Yeast Rai1p (RAI1 ortholog) physically binds and stabilizes the nuclear 5'→3' exoribonuclease Rat1p, stimulating its in vitro exoribonuclease activity. Deletion of RAI1 causes defects in 5.8S rRNA processing and 60S ribosome biogenesis that are rescued by overexpression of RAT1, placing Rai1 upstream of Rat1 in nuclear RNA metabolism. Protein purification and in vitro exoribonuclease assay, genetic epistasis (complementation by RAT1 overexpression, synthetic lethality with rat1-1), Northern blot, polysome analysis Molecular and cellular biology High 10805743
2005 RAI1 localizes to the nucleus and has transcriptional transactivation activity, as demonstrated using GFP and GAL4 DNA-binding domain fusions to Rai1 in cells. Haploinsufficiency of Rai1 in mice causes obesity and craniofacial abnormalities, establishing Rai1 as a transcriptional regulator essential for development. GFP/GAL4-fusion transactivation assay, lacZ reporter knock-in for expression mapping, mouse knockout/haploinsufficiency model Human molecular genetics High 15746153
2012 RAI1 directly regulates transcription of the circadian gene CLOCK. RAI1 haploinsufficiency in SMS patient fibroblasts and mouse hypothalamus leads to downregulation of CLOCK and downstream circadian genes including PER2, PER3, CRY1, and BMAL1, establishing RAI1 as a positive transcriptional regulator of the circadian oscillator. Reporter gene assays (CLOCK promoter luciferase), qRT-PCR in haploinsufficient fibroblasts and mouse hypothalamus, chromatin analysis American journal of human genetics High 22578325
2010 RAI1 directly regulates BDNF expression. Reporter studies showed RAI1 activates a BDNF enhancer, and Rai1 haploinsufficient mice have reduced Bdnf expression in the hypothalamus, linking RAI1 to hyperphagia and obesity through the BDNF pathway. Luciferase reporter assay (BDNF enhancer), qRT-PCR in mouse hypothalamus, mouse haploinsufficiency model with obesity phenotyping Human molecular genetics High 20663924
2012 RAI1 truncation mutations that affect only the N-terminal half of the protein cause cytoplasmic mislocalization (instead of normal nuclear localization) and abolish transcriptional activation of the endogenous BDNF enhancer target, while missense mutations in the C-terminal half retain nuclear localization but lose transactivation activity. These data demonstrate that the nuclear localization signal and transcriptional activation domain reside in separable regions of RAI1. Immunofluorescence (subcellular localization), luciferase reporter assay (BDNF enhancer), western blot, subcellular fractionation of SMS patient-derived lymphoblastoid cells PloS one High 23028815
2010 Wild-type full-length RAI1 localizes to the nucleus and activates transcription from a reporter gene, whereas frameshift mutations generating truncated N-terminal polypeptides show abnormal cytoplasmic localization. Two C-terminal half fragments localize to the nucleus but lack transactivation activity, confirming functional domain separation. Western blot, immunofluorescence, luciferase reporter assay in transfected cells BMC molecular biology Medium 20738874
2016 RAI1 preferentially occupies DNA regions near active gene promoters and promotes expression of genes involved in neural circuit assembly and neuronal communication. Pan-neural loss of Rai1 produces motor, learning, and food-intake deficits; loss in inhibitory neurons or subcortical glutamatergic neurons causes learning deficits; loss in Sim1+ or SF1+ hypothalamic cells causes obesity. ChIP-seq (Rai1 genome-wide occupancy), conditional neuron-type-specific knockout mice, behavioral analysis, electrophysiology Neuron High 27693255
2020 RAI1 regulates activity-dependent nascent transcription in neurons and is required for both suppression of synaptic upscaling in naive networks and promotion of upscaling triggered by activity silencing. Dynamic chromatin occupancy of RAI1 correlates with transcriptional changes and electrophysiological properties in Rai1-deficient neurons. Nascent RNA sequencing (EU-seq), RAI1 ChIP-seq, electrophysiology (miniature EPSCs) in primary neuron cultures from Rai1 knockout mice Cell reports High 32783930
2022 Loss of Rai1 from glutamatergic (but not GABAergic) neurons is responsible for increased seizure susceptibility in SMS mice. Rai1 deletion from Emx1-lineage glutamatergic neurons results in increased excitatory synaptic transmission and increased intrinsic excitability of dentate gyrus granule cells, identifying RAI1 as a negative regulator of dentate gyrus granule cell intrinsic and synaptic excitability. Cell-type-specific conditional knockout mice, in vivo EEG/seizure susceptibility, ex vivo patch-clamp electrophysiology, chemogenetic/chemoconvulsant challenge, brain-wide activity mapping (c-Fos) Proceedings of the National Academy of Sciences of the United States of America High 36256819
2021 Postnatal Rai1 deletion in mice causes adult-onset obesity and decreased hypothalamic Bdnf expression. Genetic overexpression of human BDNF in Rai1 heterozygous mice reverses SMS-like obesity, hyperphagia, metabolic syndrome-like features, and hyposociability, placing RAI1 upstream of BDNF in hypothalamic body-weight regulation. Inducible conditional Rai1 knockout mice, genetic rescue (Bdnf overexpression), metabolic phenotyping, stereotaxic viral injection, behavioral testing Human molecular genetics High 34463714
2023 Selective Rai1 loss from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induces obesity; Rai1 ablation decreases intrinsic excitability of PVH BDNF neurons as measured by electrophysiology. Chronic treatment of SMS mice with a TrkB agonist (LM22A-4) delayed obesity onset and partially rescued lipid profiles, insulin intolerance, and stereotypical behavior. Cell-type-specific conditional knockout (BDNF-Cre × Rai1-flox), in vivo electrophysiological recordings of PVH neurons, pharmacological TrkB agonist treatment, metabolic phenotyping eLife High 37956053
2015 Biochemical and structural studies of fungal Rai1 homologs defined a single active site that supports multiple distinct RNA 5'-end processing activities (pyrophosphohydrolase/PPH, 5'-end triphosphonucleotide hydrolase/TPH, decapping, and 5'-3' exonuclease). Crystal structures of two fungal Rai1 enzymes bound to RNA oligonucleotides revealed differences in RNA binding modes; structure-based mutagenesis of poorly conserved RNA-contacting residues substantially altered activity profiles. X-ray crystallography, in vitro RNA processing assays, structure-based site-directed mutagenesis Nucleic acids research High 26101253
2020 DXO/Rai1 family enzymes remove FAD and dephospho-CoA (dpCoA) non-canonical caps from RNA (deFADding and deCoAping activities). Crystal structures of mammalian DXO with FAD or CoA and fission yeast Rai1 with 3'-FADP showed that FAD and CoA are accommodated in the DXO/Rai1 active site in folded conformations, with the flavin/pantetheine group contacting a conserved region at the bottom of the active site tunnel that undergoes conformational changes. FAD-capped RNAs were detected in human cells and are stabilized in the absence of DXO. X-ray crystallography, in vitro decapping/deNADding assays, FAD-capQ quantification in human cells, DXO knockout cells Nucleic acids research High 32374864
2020 DXO (mammalian Rai1 homolog) catalyzes hydrolysis of RNAs bearing a 5'-hydroxyl group (5'-OH RNA) through a novel 5'-hydroxyl dinucleotide hydrolase (HDH) activity, first removing a dinucleotide. Crystal structure of DXO with a 5'-OH RNA substrate mimic at 2.0 Å provided mechanistic insight. Fission yeast Rai1 also has HDH activity, and the Rat1-Rai1 complex can completely degrade 5'-OH RNA. X-ray crystallography (2.0 Å), in vitro nuclease assays, biochemical characterization of Rai1 and DXO homologs Nucleic acids research High 31777937
2025 Cryo-EM structure of the S. cerevisiae Rat1-Rai1-Rtt103 ternary complex at 2.9 Å resolution revealed that a short segment of Rtt103 contacts Rai1 (via Pro261 and Tyr263), while the rest of Rtt103 shows no interactions with Rai1 or Rat1. The P261G/Y263A Rtt103 mutation blocks interaction with Rat1-Rai1, demonstrating that this Rai1-interaction segment recruits Rat1-Rai1 to RNA polymerase II for transcription termination. Cryo-EM structure determination (2.9 Å), site-directed mutagenesis (Rtt103 P261G/Y263A), co-purification assays Nature communications High 40188244
2013 RAI1 contains conserved chromatin-binding modules including a C-terminal ePHD/ADD-like domain (zinc finger topology), a novel nucleosome-binding domain, and an AT-hook-like region. The conserved nucleosome-binding region of RAI1 directly binds the nucleosome core and histones in vitro and in yeast interaction assays, supporting RAI1 as a histone code reader. In vitro binding assays (nucleosome/histone pulldown), yeast two-hybrid interaction studies, phylogenetic and domain analysis PloS one Medium 24205348
2014 Knockdown of Rai1 in Xenopus laevis/tropicalis using antisense morpholinos causes midface hypoplasia, malformed mouth, aberrant neural crest migration, reduced facial cartilage, axon patterning defects, decreased forebrain ventricle size, and decreased bdnf expression with increased forebrain apoptosis, establishing Rai1 as required for normal neural and craniofacial development in a vertebrate embryo model. Antisense morpholino knockdown in Xenopus, in situ hybridization, immunostaining, TUNEL assay Mechanisms of development Medium 24878353
2018 Normalizing Rai1 levels in Rai1 heterozygous mice 3–4 weeks after birth (but not 7–8 weeks) corrects expression of neural developmental pathway genes and fully reverses a social interaction deficit. Rai1 is required in both excitatory and inhibitory neurons for proper social interactions. Rai1 heterozygous mice show reduced dendritic spine density in medial prefrontal cortex; optogenetic activation of mPFC neurons improves social interaction deficit. Inducible Rai1 reactivation mouse model, RNA-seq, behavioral testing, Golgi staining (spine density), optogenetic activation Proceedings of the National Academy of Sciences of the United States of America High 30275311
2006 Restoring normal disomic Rai1 gene dosage in a mouse duplication model [Dp(11)17/Rai1(-) compound heterozygotes] was sufficient to rescue the complex physical and behavioral phenotypes of the duplication syndrome, despite continued trisomic copy number of 18 other genes in the interval, establishing RAI1 as the sole dosage-sensitive gene responsible for dup(17)(p11.2) phenotypes. Genetic epistasis using compound heterozygous mice (chromosomal duplication + Rai1 null allele), behavioral testing, body weight analysis The Journal of clinical investigation High 17024248
2009 Rai1-transgenic mice with increased Rai1 dosage show significantly impaired serotonin metabolism in whole-brain lysates (reduced serotonin turnover ratio), along with abnormal maternal behavior and altered social behavior, suggesting RAI1 regulates the serotonin pathway in a dosage-dependent manner. HPLC-based neurotransmitter measurement from whole-brain lysates, behavioral testing (pup retrieval, social interaction) in Rai1-transgenic mice Mammalian genome Medium 19319603
2017 Rai1 haploinsufficient mice are hypersensitive to light, such that light eliminates alert/active-wake behaviors. At the neural circuit level, activation of rod/cone photoreceptors and suprachiasmatic nucleus (SCN) by light was paradoxically reduced in Rai1+/- mice, while downstream activation of the ventral subparaventricular zone (vSPVZ) was increased, implicating RAI1 in processing non-visual light information from retinal input through the SCN to the vSPVZ. Wheel-running activity monitoring, immunohistochemical mapping of light-induced c-Fos in SCN and vSPVZ, pupillometry, electroretinography in Rai1+/- mice eLife Medium 28548639
2023 RAI1 forms a protein complex with TCF20, PHF14, and HMG20A in the marmoset brain. In vitro assays in human cells revealed that TCF20 regulates RAI1 protein abundance, identifying TCF20 as a regulator of RAI1 protein levels. Co-immunoprecipitation from marmoset brain tissue (mass spectrometry), in vitro overexpression/knockdown assays in human cells measuring RAI1 protein levels The Journal of comparative neurology Medium 38289192
2023 KMT2A physically associates with a PHF5A-PHF14-HMG20A-RAI1 protein subcomplex in pancreatic cancer stem cells. Targeting this complex with a KMT2A-WDR5 inhibitor reduces PCSC self-renewal, cell viability, and in vivo tumorigenicity. Co-immunoprecipitation (KMT2A with RAI1 subcomplex), pharmacological inhibition assays, in vivo tumorigenicity assays Nature communications Medium 37709746
2026 TRIM27 is a post-translational destabilizer of RAI1 protein. TRIM27 physically interacts with RAI1 and mediates K48- and K63-linked ubiquitination of RAI1, targeting it for proteasomal degradation. RAI1 degradation occurs primarily through the ubiquitin proteasome system. Knockdown of TRIM27 in SMS mouse primary neurons partially rescues SMS-associated morphological phenotypes. Forward CRISPR screen for RAI1 steady-state level regulators, Co-IP (TRIM27-RAI1 interaction), ubiquitination assays (K48/K63 linkage), proteasome inhibitor experiments, shRNA knockdown in primary neurons with morphological phenotyping Genetics High 42140622
2024 The SNP rs4925102 in the RAI1 5'-upstream region regulates RAI1 mRNA expression in an allele-specific manner. RXRα and RARα bind to the predicted RAI1 regulatory target at this locus (confirmed by ChIP assay), and chromatin conformation capture (3C) demonstrated physical chromatin looping between rs4925102 and the RAI1 promoter in human cell lines including SH-SY5Y neuroblastoma cells. Luciferase reporter gene assay, chromatin immunoprecipitation (ChIP for RXRα/RARα), chromatin conformation capture (3C assay) Genes Medium 38674394
2024 Cryo-EM and X-ray structures of the Xrn2/Rat1-Rai1-Rtt103 torpedo termination complex from S. cerevisiae and C. thermophilum revealed conserved core folds but significant variability in interaction interfaces between species. In the mesophile S. cerevisiae, Rtt103 uses an unstructured region to augment a Rai1 β-sheet; in the thermophile, Rtt103 binds a C-terminal helix of Rai1 via its CTD-interacting domain with an α-helical fold. Cryo-EM and X-ray crystallography of torpedo complexes from two organisms, structural comparison Structure High 39657659

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in RAI1 associated with Smith-Magenis syndrome. Nature genetics 248 12652298
2009 Structure and function of the 5'-->3' exoribonuclease Rat1 and its activating partner Rai1. Nature 171 19194460
2000 Saccharomyces cerevisiae RAI1 (YGL246c) is homologous to human DOM3Z and encodes a protein that binds the nuclear exoribonuclease Rat1p. Molecular and cellular biology 104 10805743
2005 RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. Journal of medical genetics 92 15788730
2010 Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome. Human molecular genetics 90 20663924
2004 Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Human genetics 85 15565467
2003 SmcR and cyclic AMP receptor protein coactivate Vibrio vulnificus vvpE encoding elastase through the RpoS-dependent promoter in a synergistic manner. The Journal of biological chemistry 85 12947096
2012 Smith-Magenis syndrome results in disruption of CLOCK gene transcription and reveals an integral role for RAI1 in the maintenance of circadian rhythmicity. American journal of human genetics 81 22578325
2000 CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2). Human molecular genetics 74 10915763
2005 Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome. Human molecular genetics 73 15746153
2018 Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men. American journal of respiratory cell and molecular biology 69 29077507
2007 Rai1 deficiency in mice causes learning impairment and motor dysfunction, whereas Rai1 heterozygous mice display minimal behavioral phenotypes. Human molecular genetics 67 17517686
2012 The bHLH Rac Immunity1 (RAI1) Is Activated by OsRac1 via OsMAPK3 and OsMAPK6 in Rice Immunity. Plant & cell physiology 66 22437844
2001 SmcR-dependent regulation of adaptive phenotypes in Vibrio vulnificus. Journal of bacteriology 65 11133972
2006 Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). The Journal of clinical investigation 59 17024248
2016 Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome. Neuron 56 27693255
2014 Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity. Molecular genetics and metabolism 56 24863970
2013 LuxR homologue SmcR is essential for Vibrio vulnificus pathogenesis and biofilm detachment, and its expression is induced by host cells. Infection and immunity 53 23897607
2021 N6-methyladenosine demethylase ALKBH5 suppresses malignancy of esophageal cancer by regulating microRNA biogenesis and RAI1 expression. Oncogene 51 34312488
2008 How much is too much? Phenotypic consequences of Rai1 overexpression in mice. European journal of human genetics : EJHG 51 18285828
2011 Regulation of cytotoxicity by quorum-sensing signaling in Vibrio vulnificus is mediated by SmcR, a repressor of hlyU. Journal of bacteriology 47 21398530
2011 Smith-Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways. Expert reviews in molecular medicine 45 21545756
2010 Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior. Current genomics 44 21629438
2003 Molecular cloning and characterization of human RAI1, a gene associated with schizophrenia. Genomics 44 12837267
2008 A consensus sequence for binding of SmcR, a Vibrio vulnificus LuxR homologue, and genome-wide identification of the SmcR regulon. The Journal of biological chemistry 42 18579523
2007 Identification and functional analysis of vibrio vulnificus SmcR, a novel global regulator. Journal of microbiology and biotechnology 42 18051765
2006 RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome. American journal of medical genetics. Part A 42 17041942
2019 Importance of OsRac1 and RAI1 in signalling of nucleotide-binding site leucine-rich repeat protein-mediated resistance to rice blast disease. The New phytologist 40 30919975
2017 RAI1 gene mutations: mechanisms of Smith-Magenis syndrome. The application of clinical genetics 40 29138588
2011 Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1) in patients with suspected Smith-Magenis syndrome without the 17p11.2 deletion. PloS one 38 21857958
2010 Crystal structure of SmcR, a quorum-sensing master regulator of Vibrio vulnificus, provides insight into its regulation of transcription. The Journal of biological chemistry 38 20178981
2006 Transcriptional regulatory cascade for elastase production in Vibrio vulnificus: LuxO activates luxT expression and LuxT represses smcR expression. The Journal of biological chemistry 36 16971386
2020 DXO/Rai1 enzymes remove 5'-end FAD and dephospho-CoA caps on RNAs. Nucleic acids research 35 32374864
2007 Penetrance of craniofacial anomalies in mouse models of Smith-Magenis syndrome is modified by genomic sequence surrounding Rai1: not all null alleles are alike. American journal of human genetics 34 17273973
2013 The fur-iron complex modulates expression of the quorum-sensing master regulator, SmcR, to control expression of virulence factors in Vibrio vulnificus. Infection and immunity 33 23716618
2015 Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome. American journal of human genetics 31 26544804
2012 RAI1 transcription factor activity is impaired in mutants associated with Smith-Magenis Syndrome. PloS one 31 23028815
2020 RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling. Cell reports 30 32783930
2010 Direct interaction between quorum-sensing regulator SmcR and RNA polymerase is mediated by integration host factor to activate vvpE encoding elastase in Vibrio vulnificus. The Journal of biological chemistry 30 20110369
2010 Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome. BMC molecular biology 30 20738874
2015 Whole exome sequencing identifies RAI1 mutation in a morbidly obese child diagnosed with ROHHAD syndrome. The Journal of clinical endocrinology and metabolism 29 25781356
2005 Diagnostic FISH probes for del(17)(p11.2p11.2) associated with Smith-Magenis syndrome should contain the RAI1 gene. American journal of medical genetics. Part A 28 15690371
2001 RAI1 is a novel polyglutamine encoding gene that is deleted in Smith-Magenis syndrome patients. Gene 28 11404004
2016 Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics. Genome medicine 26 27799067
2014 Retinoic acid induced-1 (Rai1) regulates craniofacial and brain development in Xenopus. Mechanisms of development 26 24878353
2018 Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith-Magenis syndrome. Proceedings of the National Academy of Sciences of the United States of America 25 30275311
2013 Circadian abnormalities in mouse models of Smith-Magenis syndrome: evidence for involvement of RAI1. American journal of medical genetics. Part A 25 23703963
2012 Evidence that the Vibrio vulnificus flagellar regulator FlhF is regulated by a quorum sensing master regulator SmcR. Microbiology (Reading, England) 25 22679105
2023 Pentanucleotide Repeat Insertions in RAI1 Cause Benign Adult Familial Myoclonic Epilepsy Type 8. Movement disorders : official journal of the Movement Disorder Society 21 37994247
2015 Structural and biochemical studies of the distinct activity profiles of Rai1 enzymes. Nucleic acids research 21 26101253
2014 Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions. Molecular syndromology 21 24715852
2013 A phylogenetic study of SPBP and RAI1: evolutionary conservation of chromatin binding modules. PloS one 20 24205348
2011 Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome. European journal of human genetics : EJHG 20 21897445
2017 Rai1 frees mice from the repression of active wake behaviors by light. eLife 19 28548639
2020 A novel 5'-hydroxyl dinucleotide hydrolase activity for the DXO/Rai1 family of enzymes. Nucleic acids research 18 31777937
2009 Abnormal maternal behavior, altered sociability, and impaired serotonin metabolism in Rai1-transgenic mice. Mammalian genome : official journal of the International Mammalian Genome Society 18 19319603
2021 Temporal dissection of Rai1 function reveals brain-derived neurotrophic factor as a potential therapeutic target for Smith-Magenis syndrome. Human molecular genetics 17 34463714
2004 Regulation of proinflammatory mediator production in RAW264.7 macrophage by Vibrio vulnificus luxS and smcR. FEMS immunology and medical microbiology 15 15145462
2022 Loss of Rai1 enhances hippocampal excitability and epileptogenesis in mouse models of Smith-Magenis syndrome. Proceedings of the National Academy of Sciences of the United States of America 14 36256819
2022 rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice. The Journal of biological chemistry 14 36410433
2021 The DNA binding domain of the Vibrio vulnificus SmcR transcription factor is flexible and binds diverse DNA sequences. Nucleic acids research 13 34023896
2017 Rai1 Haploinsufficiency Is Associated with Social Abnormalities in Mice. Biology 13 28448442
2016 Whole Exome Sequencing Reveals Homozygous Mutations in RAI1, OTOF, and SLC26A4 Genes Associated with Nonsyndromic Hearing Loss in Altaian Families (South Siberia). PloS one 13 27082237
2014 Dietary regimens modify early onset of obesity in mice haploinsufficient for Rai1. PloS one 13 25127133
2023 KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics. Nature communications 12 37709746
2023 Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling. eLife 12 37956053
2021 The OsSPK1-OsRac1-RAI1 defense signaling pathway is shared by two distantly related NLR proteins in rice blast resistance. Plant physiology 12 34597396
2015 Stationary-phase induction of vvpS expression by three transcription factors: repression by LeuO and activation by SmcR and CRP. Molecular microbiology 12 25869813
2012 Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1. Brain & development 12 23078968
2018 A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation. Biology 11 29794985
2023 Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant. Genes 9 37628566
2016 Evidence for genetic regulation of mRNA expression of the dosage-sensitive gene retinoic acid induced-1 (RAI1) in human brain. Scientific reports 9 26743651
2008 Diagnosing Smith-Magenis syndrome and duplication 17p11.2 syndrome by RAI1 gene copy number variation using quantitative real-time PCR. Genetic testing 9 18373405
2021 Purification of the Vibrio Quorum-Sensing Transcription Factors LuxR, HapR, and SmcR. Methods in molecular biology (Clifton, N.J.) 8 32705543
2020 Phenotypic Discovery of an Antivirulence Agent against Vibrio vulnificus via Modulation of Quorum-Sensing Regulator SmcR. ACS infectious diseases 8 33086782
2008 Distorted Mendelian transmission as a function of genetic background in Rai1-haploinsufficient mice. European journal of medical genetics 7 19116176
2022 Smith Magenis syndrome: First case of congenital heart defect in a patient with Rai1 mutation. American journal of medical genetics. Part A 6 35373511
2016 Delayed diagnosis in a house of correction: Smith-Magenis syndrome due to a de novo nonsense RAI1 variant. American journal of medical genetics. Part A 6 27311559
2016 Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy. Human genetics 6 27386852
2024 Comparative analyses of the Smith-Magenis syndrome protein RAI1 in mice and common marmoset monkeys. The Journal of comparative neurology 4 38289192
2024 Whole Exome Sequencing of a Multiplex Family of Indian Origin Identifies Variants in the RAI1 and FLII Genes within the 17p11.2 Region in Siblings with Autism and Smith Magenis Syndrome. Molecular syndromology 4 39634244
2010 Regulation of the Vibrio vulnificus vvpE expression by cyclic AMP-receptor protein and quorum-sensing regulator SmcR. Microbial pathogenesis 4 20638468
2018 Production and characterization of CSSI003 (2961) human induced pluripotent stem cells (iPSCs) carrying a novel puntiform mutation in RAI1 gene, Causative of Smith-Magenis syndrome. Stem cell research 3 29494847
2023 A case of Smith-Magenis syndrome with skin manifestations caused by a novel locus mutation in the RAI1 gene. The Journal of international medical research 2 37756600
2022 A unique Smith-Magenis patient with a de novo intragenic deletion on the maternally inherited overexpressed RAI1 allele. European journal of human genetics : EJHG 2 35821519
2025 Molecular basis for the interaction between Saccharomyces cerevisiae Rtt103 and the Rat1-Rai1 complex. Nature communications 1 40188244
2025 Deletion of RAI1 noncoding exons 1-2 causes Smith-Magenis syndrome. Journal of genetics 1 40386916
2024 Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G). Genes 1 38674394
2024 Novel RAI1:c.2736delC Variant in Smith-Magenis Syndrome: Identification by Whole Genome Sequencing and Joint Analysis. Journal of personalized medicine 1 39338155
2024 Assembly of the Xrn2/Rat1-Rai1-Rtt103 termination complexes in mesophilic and thermophilic organisms. Structure (London, England : 1993) 1 39657659
2023 Transcription termination complex, Rtt103-Rai1-Rat1, regulates sub-telomeric transcripts in Saccharomyces cerevisiae. RNA biology 1 36974034
2021 RAI1 alternate probe identifies additional gastroesophageal adenocarcinoma cases as amplified following equivocal HER2 fluorescence in situ hybridization testing: experience from a national reference laboratory. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 1 34663915
2026 Ligand binding drives proteolysis of the SmcR master transcription factor and controls quorum sensing-state transitions in Vibrio species. mBio 0 41615159
2026 Behavioral Phenotype and Neuropsychological Profile of an Adult With Smith-Magenis Syndrome due to a Previously Unreported RAI1 Mutation: A Case Report. Clinical case reports 0 41767072
2026 CRISPR screening identifies TRIM27 as a destabilizer of the Smith-Magenis syndrome protein RAI1. Genetics 0 42140622
2026 Distinct Neuropsychiatric Profiles Associated With 17p11.2 Deletions and RAI1 Variants in Smith-Magenis Syndrome. American journal of medical genetics. Part A 0 42178606
2025 Generation and characterization of the CSSi021-A (15665) human induced pluripotent stem cell line from a Smith-Magenis syndrome patient with a heterozygous RAI1 mutation. Stem cell research 0 40311325
2024 Overlapping hearing and communication profiles for the deletion and the RAI1 variant form of Smith-Magenis Syndrome (SMS). Journal of communication disorders 0 39213791

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