Affinage

CIRSR

Corepressor of RBPJ and splicing regulator · UniProt Q86X95

Length
450 aa
Mass
52.3 kDa
Annotated
2026-06-09
36 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIRSR (CIR1) is a metazoan-specific spliceosomal protein and CSL/Notch corepressor that operates at the interface of pre-mRNA splicing and transcriptional regulation of the Notch pathway (PMID:33007253, PMID:34798064). Within the human spliceosomal C complex, CIR1 is spatially integrated into the catalytic machinery where it stabilizes protein domains and RNA structures that are rearranged during the Bact-to-C transition (PMID:33007253). In Notch signaling, CIR1 is bound directly by RYBP, an interaction that promotes RBPJ association with the Notch intracellular domain (NICD) to activate Notch target genes; in the absence of RYBP, CIR1 instead competes with RBPJ for NICD binding, repressing Notch signaling and driving neuronal differentiation of embryonic neural progenitors (PMID:34798064). This corepressor role is conserved: the C. elegans ortholog CIR-1 acts as a CSL corepressor that, together with MOG-3 and MEP-1, regulates germline meiosis and sex determination (PMID:20478293).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1998 Low

    Before any function was known, it was unclear whether CIR1 expression tracked with cellular states, and the first link came from associating its transcript level with cellular immortalization.

    Evidence mRNA differential display and Northern blot comparing pre-immortal vs. immortal human cell clones and tumor-derived lines

    PMID:9771976

    Open questions at the time
    • Expression correlation only; no functional assay linking CIR1 activity to immortalization mechanism
    • Does not define a molecular function for the protein
  2. 2010 Medium

    Whether CIR1's corepressor role was conserved and what partners it used in vivo was unknown; work in C. elegans placed the ortholog CIR-1 in a nuclear complex controlling germ cell fate.

    Evidence Yeast two-hybrid and Co-IP showing MOG-3 binds CIR-1 and MEP-1, with genetic epistasis downstream of GLP-1/Notch in C. elegans

    PMID:20478293

    Open questions at the time
    • Mapped in the worm ortholog, not human CIR1
    • Biochemical mechanism of CSL corepression not resolved
    • Direct link between complex composition and Notch output not established at molecular level
  3. 2014 Low

    It was unknown whether CIR1 influences cell cycle progression; RNAi of the worm ortholog tied its loss to accelerated division, phenocopying RNA Pol II inhibition and implicating transcriptional regulation.

    Evidence Semi-automated nuclear tracking after cir-1 RNAi in C. elegans embryos, with epistasis to RNA polymerase II inhibition

    PMID:25446273

    Open questions at the time
    • Single RNAi phenotype in ortholog; no direct biochemical mechanism for CIR1
    • Causal connection between transcriptional role and division timing not defined
  4. 2020 High

    The molecular context of CIR1 in the spliceosome was unresolved until a high-resolution structure placed it within the catalytic C complex as a stabilizing component.

    Evidence Cryo-EM of the human spliceosomal C complex at 3.4 Å core resolution with crosslinking/MS architecture assignment

    PMID:33007253

    Open questions at the time
    • Structural placement does not establish a catalytic or regulatory function for CIR1 in splicing
    • Whether CIR1's spliceosomal and Notch corepressor roles are mechanistically linked is unaddressed
  5. 2021 Medium

    How CIR1 switches between activating and repressing Notch was unknown; RYBP was identified as a direct partner that toggles CIR1 between promoting RBPJ–NICD binding and competing with RBPJ.

    Evidence Reciprocal Co-IP for RYBP–CIR1 interaction, Rybp loss-of-function with Notch readouts, and Hes5 rescue in embryonic neural progenitors

    PMID:34798064

    Open questions at the time
    • Structural basis of competition for NICD binding not determined
    • Single lab using Co-IP and knockdown; reciprocal validation in other cell types absent
    • Connection to CIR1's spliceosomal function not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether CIR1's role as a spliceosomal C-complex component and its role as a Notch/CSL corepressor are functionally coupled or represent independent activities.
  • No study integrates the splicing and transcriptional corepressor functions
  • No human structural or biochemical mechanism for CSL corepression
  • No identified splicing substrates dependent on CIR1

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-8953854 Metabolism of RNA 1
Partners
MEP-1MOG-3RBPJRYBP
Complex memberships
spliceosomal C complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Cryo-EM structure of the human spliceosomal C complex at 3.4 Å core resolution revealed that the metazoan-specific protein CIR1 is spatially organized within the C complex, where it stabilizes functionally important protein domains and RNA structures that are rearranged/repositioned during the Bact-to-C transition. Cryo-EM structure determination at 3.4 Å (core) with protein crosslinking/MS for molecular architecture assignment Molecular cell High 33007253
2021 RYBP directly interacts with CIR1, and this interaction facilitates binding of RBPJ to the Notch intracellular domain (NICD), thereby activating Notch signaling. Upon Rybp loss, CIR1 competes with RBPJ to bind NICD, inhibiting Notch signaling and promoting neuronal differentiation of embryonic neural progenitor cells. Co-immunoprecipitation (direct interaction of RYBP and CIR1); loss-of-function (Rybp depletion) with Notch signaling readouts; rescue experiment with Hes5 overexpression Stem cell reports Medium 34798064
2010 In C. elegans, MOG-3 binds to the CSL co-repressor CIR-1 (ortholog of mammalian CIR1) and to MEP-1 in the nucleus, and this complex regulates germ cell development including meiosis and sex determination; the mammalian CIR1 homolog is noted to counter Notch signaling. Yeast two-hybrid and co-immunoprecipitation demonstrating MOG-3 interaction with CIR-1; genetic epistasis (mog-3 mutant phenotypes downstream of GLP-1/Notch) Developmental biology Medium 20478293
1998 CIR1 (identical to CROC1/UEV-1) transcript is upregulated 5–6-fold in immortalized human cells immediately following proliferative crisis compared to pre-immortal counterparts, and is also elevated in a variety of immortal tumor-derived human cell lines relative to normal tissue. mRNA differential display comparing genetically matched pre-immortal and immortal human cell clones; Northern blot validation Oncogene Low 9771976
2014 RNAi inhibition of cir-1 (C. elegans ortholog of CIR1) accelerated cell division timing in specific cells of the AB lineage during early embryogenesis, a phenotype also produced by inhibition of RNA polymerase II, suggesting CIR1 function is linked to transcriptional regulation that normally delays cell cycle progression. Semi-automated nuclear tracking of all nuclei during C. elegans early development following RNAi knockdown; epistasis with RNA polymerase II inhibition Developmental biology Low 25446273

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans. PLoS biology 179 17121456
2010 HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans. PLoS pathogens 133 21124817
2008 Iron source preference and regulation of iron uptake in Cryptococcus neoformans. PLoS pathogens 131 18282105
2007 Iron and fungal pathogenesis: a case study with Cryptococcus neoformans. Cellular microbiology 86 18042257
2011 Toward an integrated model of capsule regulation in Cryptococcus neoformans. PLoS pathogens 82 22174677
2013 An encapsulation of iron homeostasis and virulence in Cryptococcus neoformans. Trends in microbiology 60 23810126
2014 Defects in phosphate acquisition and storage influence virulence of Cryptococcus neoformans. Infection and immunity 54 24711572
2018 The Monothiol Glutaredoxin Grx4 Regulates Iron Homeostasis and Virulence in Cryptococcus neoformans. mBio 50 30514787
1998 Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha. Molecular endocrinology (Baltimore, Md.) 39 9482666
2020 Structural Insights into the Roles of Metazoan-Specific Splicing Factors in the Human Step 1 Spliceosome. Molecular cell 38 33007253
2012 Influence of iron regulation on the metabolome of Cryptococcus neoformans. PloS one 32 22911836
1998 Up-regulation of CIR1/CROC1 expression upon cell immortalization and in tumor-derived human cell lines. Oncogene 32 9771976
2020 A Transcriptional Regulatory Map of Iron Homeostasis Reveals a New Control Circuit for Capsule Formation in Cryptococcus neoformans. Genetics 25 32580959
2015 Gallic acid production under anaerobic submerged fermentation by two bacilli strains. Microbial cell factories 25 26715179
2014 Comprehensive single cell-resolution analysis of the role of chromatin regulators in early C. elegans embryogenesis. Developmental biology 20 25446273
2014 A functional polymorphism in CSF1R gene is a novel susceptibility marker for lung cancer among never-smoking females. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 19 25144241
2018 Synthetic Cargo Internalization Receptor System for Nanoparticle Tracking of Individual Cell Populations by Fluorine Magnetic Resonance Imaging. ACS nano 18 30372619
2010 The iron-responsive, GATA-type transcription factor Cir1 influences mating in Cryptococcus neoformans. Molecules and cells 18 21120626
2024 The interplay between electron transport chain function and iron regulatory factors influences melanin formation in Cryptococcus neoformans. mSphere 17 38687055
2003 Identification of long intergenic repeat sequences associated with DNA methylation sites in Caulobacter crescentus and other alpha-proteobacteria. Journal of bacteriology 17 12897020
2021 Coordinated regulation of iron metabolism in Cryptococcus neoformans by GATA and CCAAT transcription factors: connections with virulence. Current genetics 16 33760942
2021 The monothiol glutaredoxin Grx4 influences thermotolerance, cell wall integrity, and Mpk1 signaling in Cryptococcus neoformans. G3 (Bethesda, Md.) 15 34542604
2011 Iron influences the abundance of the iron regulatory protein Cir1 in the fungal pathogen Cryptococcus neoformans. FEBS letters 15 21963719
2010 The C. elegans sex determination protein MOG-3 functions in meiosis and binds to the CSL co-repressor CIR-1. Developmental biology 15 20478293
2023 Effects of Maize-Crop Rotation on Soil Physicochemical Properties, Enzyme Activities, Microbial Biomass and Microbial Community Structure in Southwest China. Microorganisms 13 38004632
2021 RYBP modulates embryonic neurogenesis involving the Notch signaling pathway in a PRC1-independent pattern. Stem cell reports 13 34798064
1994 An operator associated with autoregulation of the repressor gene in actinophage phiC31 is found in highly conserved copies in intergenic regions in the phage genome. Nucleic acids research 12 8139924
2023 Factors Influencing the Nitrogen-Source Dependent Flucytosine Resistance in Cryptococcus Species. mBio 7 36656038
2021 The complete mitochondrial genome of Coriandrum sativum. Mitochondrial DNA. Part B, Resources 5 34345704
2016 Polymorphisms in cancer-related pathway genes and lung cancer. The European respiratory journal 5 27587543
2019 Impact of iron chelators on growth and expression of iron-related genes of Cryptococcus species. Journal de mycologie medicale 4 31706700
2024 The interplay between electron transport chain function and iron regulatory factors influences melanin formation in Cryptococcus neoformans. bioRxiv : the preprint server for biology 1 38405941
2008 [Mechanism of conditioned immune response in curing bronchial asthma in mice]. Zhonghua er ke za zhi = Chinese journal of pediatrics 1 19134256
2026 Integrative transcriptomic analysis reveals alternative splicing programs in sepsis-induced myocardial injury across dual mouse models. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 0 41843179
2025 The kinase Bud32 regulates iron homeostasis in fungal pathogen Cryptococcus neoformans. Frontiers in immunology 0 40787456
2020 Methods to Validate Binding and Kinetics of "Proximity-Inducing" Covalent Immune-Recruiting Molecules. Current protocols in chemical biology 0 33326159

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