Affinage

RCL1

RNA 3'-terminal phosphate cyclase-like protein · UniProt Q9Y2P8

Length
373 aa
Mass
40.8 kDa
Annotated
2026-06-10
59 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RCL1 is an essential nucleolar component of the small subunit (SSU) processome that drives pre-rRNA processing during ribosome biogenesis, where its activity co-transcriptionally separates the rRNA precursors destined for the small and large ribosomal subunits (PMID:10790377, PMID:21849504). In yeast, recombinant Rcl1 is the endonuclease that cleaves pre-rRNA at site A2, and active-site mutations disrupt A2 processing in vitro and in vivo; its structure defines a novel nuclease class with overall homology to RNA cyclase enzymes but lacking their adenylyltransferase activity (PMID:21849504, PMID:21367972). Rcl1 is delivered to pre-ribosomes by the essential GTPase Bms1: the two form a GTP-dependent subcomplex with U3 snoRNA in which Rcl1 promotes GDP/GTP exchange on Bms1, and this Bms1–Rcl1 module is one of the major structural modules visualized in the assembled 90S pre-ribosome (PMID:16307926, PMID:16376378, PMID:27419870). In human cells the BMS1/RCL1 subcomplex joins the SSU processome after initial pre-rRNA association, and RCL1 protein stability and nucleolar entry depend on its physical interaction with BMS1, with loss of this interaction triggering ubiquitin–proteasome degradation (PMID:19332556, PMID:37451810). Rcl1's access to its cleavage site is gated by Rrp5, which blocks cleavage until domain I of 25S rRNA is transcribed and Noc1/Noc2 binding switches Rrp5's RNA-binding mode, coupling 40S maturation to 60S assembly progression (PMID:31217256). Across organisms the precise cleavage site differs—site A2 in yeast versus the A1-site in zebrafish, where rcl1 knockout causes small liver and exocrine pancreas and larval lethality—and human RCL1 active-site mutation did not impair 18S production, indicating organism-specific deployment of the enzyme (PMID:27034467, PMID:34019640). RCL1 transcription is directly activated by c-Myc (PMID:27602772).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 High

    Established RCL1 as an essential nucleolar factor for early pre-rRNA processing, placing it at the heart of small-subunit biogenesis rather than as a structural U3 snoRNP component.

    Evidence Genetic depletion, Co-IP, sucrose gradient sedimentation, and nucleolar localization in yeast

    PMID:10790377

    Open questions at the time
    • Did not determine whether Rcl1 is itself the catalytic enzyme or a cofactor
    • Mechanism of recruitment to pre-ribosomes unknown
  2. 2005 High

    Defined how Rcl1 reaches pre-ribosomes by showing that the GTPase Bms1 delivers it in a GTP-dependent manner, and that Rcl1 reciprocally activates Bms1 nucleotide exchange within a U3-containing subcomplex.

    Evidence Thermodynamic binding assays, yeast Bms1 mutants, and in vitro reconstitution of the GTP-dependent subcomplex

    PMID:16307926 PMID:16376378

    Open questions at the time
    • Did not establish Rcl1 catalytic function
    • Structural basis of the Bms1–Rcl1 interface not resolved
  3. 2011 High

    Identified Rcl1 as the A2-site endonuclease and provided its atomic structure, answering whether it is catalytic and defining it as a new nuclease class.

    Evidence In vitro endonuclease assay with recombinant Rcl1, active-site mutagenesis with in vivo validation, and X-ray crystallography in yeast

    PMID:21367972 PMID:21849504

    Open questions at the time
    • Catalytic mechanism and metal/residue requirements not fully defined
    • Conserved oxyanion-binding site mutations were dispensable, leaving catalytic residues unidentified
  4. 2009 Medium

    Placed the BMS1/RCL1 subcomplex within the human SSU processome and established that it associates after initial pre-rRNA assembly.

    Evidence Reciprocal Co-IP, sucrose gradient sedimentation, and siRNA depletion in human cells

    PMID:19332556

    Open questions at the time
    • Did not test whether human RCL1 is catalytically active
    • Order of module recruitment relative to other processome components incomplete
  5. 2014 Medium

    Extended Rcl1's processing role to mammals, linking its activity to ITS1 cleavages required for small-subunit maturation.

    Evidence siRNA knockdown with RAMP pre-rRNA ratio analysis by Northern blot in mouse cells and tissues

    PMID:25190460

    Open questions at the time
    • Did not establish whether mouse Rcl1 cleaves directly or stimulates cleavage
    • Precise cleavage site not mapped
  6. 2016 High

    Resolved the structural placement of the Bms1–Rcl1 module within the assembled 90S pre-ribosome, and revealed a species discrepancy by showing human RCL1 active-site mutation did not impair 18S production.

    Evidence Cryo-EM of the C. thermophilum 90S pre-ribosome; in vivo mutagenesis of human RCL1

    PMID:27034467 PMID:27419870

    Open questions at the time
    • Human catalytic contribution to cleavage remains unresolved
    • Whether another nuclease substitutes for RCL1 in human cells not determined here
  7. 2019 High

    Explained how Rcl1 cleavage is temporally gated, showing Rrp5 blocks access until 25S domain I transcription and Noc1/Noc2 binding licenses cleavage, coupling 40S and 60S assembly.

    Evidence Quantitative RNA binding and in vitro cleavage assays with in vivo genetic epistasis (Noc1 mutants, Rcl1 overexpression rescue) in yeast

    PMID:31217256

    Open questions at the time
    • Structural basis of the Rrp5 RNA-binding-mode switch not visualized
    • Conservation of this checkpoint beyond yeast untested
  8. 2021 High

    Demonstrated organism-specific cleavage and physiological requirement, with zebrafish Rcl1 acting at the A1-site and its loss causing organ-specific defects and lethality.

    Evidence Zebrafish rcl1 knockout, cleavage-site mapping, RNA-seq, and phenotypic analysis

    PMID:34019640

    Open questions at the time
    • Mechanistic basis for A1- vs A2-site preference across species unexplained
    • Tissue-selective vulnerability of liver/pancreas not mechanistically dissected
  9. 2022 Medium

    Defined the dependence of RCL1 stability and nucleolar localization on BMS1 binding, with proteasomal turnover when the interaction is lost, and positioned Rcl1 within Bms1's broader rDNA transcription–replication balancing role.

    Evidence Co-IP mapping the interaction domain, proteasome inhibitor experiments, ChIP-seq, and zebrafish genetic rescue

    PMID:34791311 PMID:37451810

    Open questions at the time
    • E3 ligase responsible for RCL1 degradation not identified
    • Direct role of Rcl1 (vs Bms1) in transcription–replication coordination unclear
  10. 2021 Medium

    Identified upstream transcriptional control of RCL1 by c-Myc.

    Evidence ChIP, dual-luciferase reporter, and EMSA in HEK293T cells

    PMID:27602772

    Open questions at the time
    • Physiological conditions driving c-Myc–dependent RCL1 expression not defined
    • Single cell-line context

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether human RCL1 retains catalytic endonuclease activity or serves a non-catalytic scaffolding role within the SSU processome remains unresolved given the negative human mutagenesis result.
  • No human in vitro cleavage reconstitution
  • Identity of the functional A1/A2 endonuclease in human cells unconfirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 2 GO:0003723 RNA binding 1 GO:0016787 hydrolase activity 1
Localization
GO:0005730 nucleolus 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
BMS1RRP5U3 SNORNA
Complex memberships
Bms1–Rcl1–U3 snoRNA subcomplexSSU processome (90S pre-ribosome)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Rcl1p (yeast RCL1 ortholog) is an essential nucleolar protein required for pre-rRNA processing at sites A0, A1, and A2; its depletion leads to a strong decrease in 18S rRNA and 40S ribosomal subunit levels. Rcl1p co-immunoprecipitates with U3 snoRNP components but is not a structural component of U3 snoRNP; most Rcl1p sediments with 70–80S pre-ribosomal particles. Genetic depletion/inactivation in yeast, immunoprecipitation, sucrose gradient sedimentation, nucleolar localization by microscopy The EMBO journal High 10790377
2005 Bms1 (an essential GTPase) delivers Rcl1 to pre-ribosomes in a GTP-dependent manner. Rcl1 binding to Bms1 is thermodynamically coupled to GTP and U3 snoRNA binding; a Bms1 mutant defective for Rcl1 binding severely limits Rcl1 recruitment to pre-ribosomes. The C-terminal domain of Bms1 acts as an intramolecular GTPase-activating protein. Thermodynamic binding assays, yeast genetics with Bms1 mutants, pre-ribosome association assays Molecular cell High 16307926
2005 Bms1, Rcl1, and U3 snoRNA form a stable GTP-dependent subcomplex; Rcl1 activates Bms1 by promoting GDP/GTP exchange, analogous to ribosome-promoted nucleotide exchange in translation elongation factor EF-G. GTP binding (but not GDP) is required for stable subcomplex formation. Quantitative thermodynamic analysis of GTP-dependent subcomplex formation in vitro Journal of molecular biology High 16376378
2011 Recombinant Rcl1 cleaves pre-rRNA at site A2 in vitro in an endonucleolytic reaction sensitive to nearby RNA mutations that inhibit cleavage in vivo. Mutations in Rcl1 disrupt rRNA processing at site A2 both in vivo and in vitro, establishing Rcl1 as the endonuclease responsible for the A2 cleavage that co-transcriptionally separates rRNAs destined for the small and large ribosomal subunits. Rcl1 defines a novel class of nucleases with no homology to other known endonucleases. In vitro endonuclease assay with recombinant Rcl1, site-directed mutagenesis, in vivo rRNA processing assays The Journal of biological chemistry High 21849504
2011 Crystal structure of yeast Rcl1 at 2.6 Å resolution reveals a modular 4-domain architecture with overall homology to RNA cyclase (Rtc) enzymes but local differences that explain why Rcl1 lacks the metal-dependent adenylyltransferase activity of Rtc enzymes. Mutations in and around a conserved oxyanion-binding site did not affect Rcl1 activity in vivo, arguing against a catalytic or RNA-binding role for this site. X-ray crystallography, in vivo mutagenesis of putative active-site residues RNA (New York, N.Y.) High 21367972
2009 In human cells, the BMS1/RCL1 subcomplex is a component of the SSU processome, a large machine required for 18S rRNA processing. The BMS1/RCL1 subcomplex is absent from a novel 50S U3 snoRNP assembly intermediate that accumulates when pre-rRNA transcription is blocked or tUTP proteins are depleted, indicating BMS1/RCL1 join the processome after initial pre-rRNA association. Co-immunoprecipitation, sucrose gradient sedimentation, siRNA depletion Molecular and cellular biology Medium 19332556
2014 Knockdown of mouse Rcl1 impairs endonucleolytic cleavages of pre-rRNA in the ITS1 region required for small ribosomal subunit maturation, as characterized by RAMP (Ratio Analysis of Multiple Precursors) profiling. The data suggest that completion of early small-subunit maturation (requiring Rcl1) triggers release from the common pre-rRNA transcript by stimulating cleavage at the proximal ITS1 site. siRNA knockdown, RAMP pre-rRNA ratio analysis by Northern blotting in mouse cells and tissues Nucleic acids research Medium 25190460
2016 Cryo-EM structure of the Chaetomium thermophilum 90S pre-ribosome identifies the Bms1–Rcl1 module as one of five major modules organized around 5'-ETS and partially folded 18S rRNA within the 90S particle architecture. Cryo-EM structure determination of the 90S pre-ribosome Cell High 27419870
2016 In human cells, mutation of the potential A2-site endonuclease RCL1 did not affect 18S rRNA production, whereas an intact PIN domain in UTP24 was required for accurate cleavages at sites 1 and 2a. This negative result for human RCL1 contrasts with yeast data where Rcl1 is the A2 endonuclease. In vivo mutagenesis of human RCL1 active-site residues, pre-rRNA processing analysis Nucleic acids research Medium 27034467
2019 Rrp5 blocks Rcl1 access to the nascent pre-rRNA cleavage site early during ribosome assembly, thereby delaying separation of small and large subunit pre-rRNAs until domain I of 25S rRNA is transcribed. Upon transcription of domain I, 60S assembly factors Noc1/Noc2 bind both this RNA and Rrp5, changing Rrp5's RNA-binding mode to permit Rcl1-mediated cleavage. Overexpression of wild-type but not catalytically inactive Rcl1 rescues subunit separation defects caused by Noc1 HEAT-repeat mutants in vivo. Quantitative RNA binding assays, in vitro cleavage assays, genetic epistasis with Noc1 mutants and Rcl1 overexpression in yeast RNA (New York, N.Y.) High 31217256
2021 In zebrafish, depletion of Rcl1 mainly impairs cleavage at the A1-site (the link between 5'ETS and 18S rRNA) rather than the A2-site as in yeast. rcl1−/− mutants exhibit small liver and exocrine pancreas and die before 15 days post-fertilization. RNA-seq reveals up-regulation of a cohort of ribosome biogenesis and tRNA production genes upon Rcl1 deficiency. Zebrafish rcl1 knockout, pre-rRNA processing site mapping by primer extension/Northern blotting, RNA-seq, phenotypic characterization Nucleic acids research High 34019640
2022 RCL1 protein stability and nucleolar localization depend on its physical interaction with BMS1. When this interaction is disrupted, RCL1 is degraded via the ubiquitination–proteasome pathway. Overexpression of RCL1 in BMS1-knockdown cells partially rescues defects in 18S rRNA processing and cell proliferation. Hepatocyte-specific overexpression of Rcl1 rescues zebrafish liver development in a bms1l substitution (but not knockout) mutant, attributed to residual nucleolar entry of Rcl1 in the former. Co-immunoprecipitation identifying RCL1-interacting domain in BMS1, proteasome inhibitor experiments, zebrafish genetic rescue experiments, cell proliferation and rRNA processing assays Journal of molecular cell biology High 37451810
2022 Zebrafish Bms1 interacts with Rcl1 and also with Ttf1 (a replication fork barrier binding protein). Loss of Bms1l upregulates rDNA transcription, causes replication-fork stall, and arrests the cell cycle at S-to-G2 transition. Bms1 GTPase activity is required to disassociate the Ttf1–RFB complex, balancing rDNA transcription and replication during S-phase. Co-immunoprecipitation (Bms1–Rcl1 and Bms1–Ttf1), ChIP-seq for Ttf1 RFB sites, zebrafish loss-of-function genetic analysis, cell cycle and DNA damage marker analysis Journal of molecular cell biology Medium 34791311
2021 c-Myc directly occupies predicted transcription factor binding sites in the RCL1 promoter region, as confirmed by ChIP assay in HEK293T cells overexpressing ectopic c-Myc, and dual-luciferase reporter assays demonstrated c-Myc functional relevance for RCL1 transcriptional regulation. ChIP assay, dual-luciferase reporter assay, EMSA Oncotarget Medium 27602772

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Architecture of the 90S Pre-ribosome: A Structural View on the Birth of the Eukaryotic Ribosome. Cell 181 27419870
2000 Rcl1p, the yeast protein similar to the RNA 3'-phosphate cyclase, associates with U3 snoRNP and is required for 18S rRNA biogenesis. The EMBO journal 82 10790377
2005 A potential role for RNA interference in controlling the activity of the human LINE-1 retrotransposon. Nucleic acids research 80 15701756
2005 An essential GTPase promotes assembly of preribosomal RNA processing complexes. Molecular cell 69 16307926
2014 Detection and quantification of hepatitis A virus and norovirus in Spanish authorized shellfish harvesting areas. International journal of food microbiology 64 25462922
2011 Rcl1 protein, a novel nuclease for 18 S ribosomal RNA production. The Journal of biological chemistry 62 21849504
2009 A novel small-subunit processome assembly intermediate that contains the U3 snoRNP, nucleolin, RRP5, and DBP4. Molecular and cellular biology 59 19332556
2014 Two orthogonal cleavages separate subunit RNAs in mouse ribosome biogenesis. Nucleic acids research 57 25190460
2016 The PIN domain endonuclease Utp24 cleaves pre-ribosomal RNA at two coupled sites in yeast and humans. Nucleic acids research 50 27034467
2015 Small regulatory RNA-induced growth rate heterogeneity of Bacillus subtilis. PLoS genetics 38 25790031
2012 Early and late peritoneal and hepatic changes in goats immunized with recombinant cathepsin L1 and infected with Fasciola hepatica. Journal of comparative pathology 36 23083835
2005 GTP-dependent formation of a ribonucleoprotein subcomplex required for ribosome biogenesis. Journal of molecular biology 34 16376378
2016 Evaluation of Circulatory RNA-Based Biomarker Panel in Hepatocellular Carcinoma. Molecular diagnosis & therapy 32 27113935
2012 Ribosome biogenesis factor Bms1-like is essential for liver development in zebrafish. Journal of genetics and genomics = Yi chuan xue bao 29 23021545
2017 A rare missense variant in RCL1 segregates with depression in extended families. Molecular psychiatry 28 28322274
2017 The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsids. Journal of hepatology 28 29113909
2019 Detection of Hepatitis E Virus in Shellfish Harvesting Areas from Galicia (Northwestern Spain). Viruses 27 31284466
1997 An antisense RNA in IS30 regulates the translational expression of the transposase. Biological chemistry 26 9461341
2020 Preclinical Studies of the Off-Target Reactivity of AFP158-Specific TCR Engineered T Cells. Frontiers in immunology 24 32395117
2020 An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson's Disease Risk and Progression in the PPMI Cohort. International journal of molecular sciences 24 32911699
2016 c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma. Oncotarget 23 27602772
2019 Dynamic Methylation of an L1 Transduction Family during Reprogramming and Neurodifferentiation. Molecular and cellular biology 19 30692270
2011 Crystal structure of Rcl1, an essential component of the eukaryal pre-rRNA processosome implicated in 18s rRNA biogenesis. RNA (New York, N.Y.) 19 21367972
2022 Maize RNA 3'-terminal phosphate cyclase-like protein promotes 18S pre-rRNA cleavage and is important for kernel development. The Plant cell 17 35167702
2021 Rcl1 depletion impairs 18S pre-rRNA processing at the A1-site and up-regulates a cohort of ribosome biogenesis genes in zebrafish. Nucleic acids research 16 34019640
2021 RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes. Molecular psychiatry 15 33597717
2019 Transcriptome Analysis Identifies an Attenuated Local Immune Response in Invasive Nonfunctioning Pituitary Adenomas. Endocrinology and metabolism (Seoul, Korea) 15 31565884
2017 Comparative assessment of recombinant and native immunogenic forms of Fasciola hepatica proteins for serodiagnosis of sheep fasciolosis. Parasitology research 15 29199372
2019 Rrp5 establishes a checkpoint for 60S assembly during 40S maturation. RNA (New York, N.Y.) 14 31217256
2020 Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis. Molecular brain 12 33187550
2018 Line-1: Implications in the etiology of cancer, clinical applications, and pharmacologic targets. Mutation research. Reviews in mutation research 12 30454683
2022 The expression of GapA and CrmA correlates with the Mycoplasma gallisepticum in vitro infection process in chicken TOCs. Veterinary research 9 36056451
2013 Peripheral blood lymphocyte subsets in Fasciola hepatica infected and immunised goats. Veterinary immunology and immunopathology 9 23838471
2023 Dengue Virus Capsid Protein Facilitates Genome Compaction and Packaging. International journal of molecular sciences 8 37175867
2016 RNA 3'-terminal phosphate cyclases and cyclase-like proteins. Postepy biochemii 8 28132487
2022 Pain-Related Abnormal Neuronal Synchronization of the Nucleus Accumbens in Parkinson's Disease. Brain sciences 7 35053828
2016 Association of BAK1 single nucleotide polymorphism with a risk for dengue hemorrhagic fever. BMC medical genetics 7 27401010
2022 Nucleolar GTPase Bms1 displaces Ttf1 from RFB-sites to balance progression of rDNA transcription and replication. Journal of molecular cell biology 6 34791311
2022 Rcl1 suppresses tumor progression of hepatocellular carcinoma: a comprehensive analysis of bioinformatics and in vitro experiments. Cancer cell international 6 35264160
1986 Synthesis of in vitro Co1E1 transcripts with 5'-terminal ribonucleotides that exhibit noncomplementarity with the DNA template. Biochemistry 6 3024712
2022 Integration of three machine learning algorithms identifies characteristic RNA binding proteins linked with diagnosis, immunity and pyroptosis of IgA nephropathy. Frontiers in genetics 5 36246620
1986 Mitomycin C-induced bidirectional transcription from the colicin E1 promoter region in plasmid ColE1. Biochimica et biophysica acta 5 3092859
2024 Stability and function of RCL1 are dependent on the interaction with BMS1. Journal of molecular cell biology 4 37451810
2021 Identification of multiple RNAs using feature fusion. Briefings in bioinformatics 4 33971667
2020 Fine Mapping to Identify the Functional Genetic Locus for Red Coloration in Pyropia yezoensis Thallus. Frontiers in plant science 4 32655600
2025 Whole-genome sequencing reveals individual and cohort level insights into chromosome 9p syndromes. Genome medicine 3 41137173
2024 The effects of RT-qPCR standards on reproducibility and comparability in monitoring SARS-CoV-2 levels in wastewater. Scientific reports 3 39462074
2019 Neutrophil GM-CSF signaling in inflammatory bowel disease patients is influenced by non-coding genetic variants. Scientific reports 3 31235766
2002 Stereochemistry of (E)- and (Z)-1,1'-dichlorobifluorenylidenes, substituted overcrowded fullerene fragments. Enantiomer 2 12643306
2025 Whole-Genome Sequencing Reveals Individual and Cohort Level Insights into Chromosome 9p Syndromes. medRxiv : the preprint server for health sciences 1 40196253
2026 Bimetallic CuCo-based metal-organic framework/graphene oxide composite-modified electrode as an efficient miRNA-208a detection biosensing platform. Journal of colloid and interface science 0 41855910
2026 Multi-omics integration identifies ribosome biogenesis-active macrophage subpopulation and its key gene GNL2 in driving liver hepatocellular carcinoma progression and mechanisms. Cancer cell international 0 42135716
2025 MORE-RNAseq: a pipeline for quantifying retrotransposition-capable LINE1 expression based on RNA-seq data. Frontiers in bioinformatics 0 40475058
2025 Investigation of the role of the LC3 conjugation system in autophagy for human reward system reactivity. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 0 40576538
2024 Roles of Nucleolar Factor RCL1 in Itraconazole Resistance of Clinical Candida albicans Under Different Stress Conditions. Infection and drug resistance 0 38433785
2020 Evaluation of Gelatinolytic and Collagenolytic Activity of Fasciola hepatica Recombinant Cathepsin-L1. Iranian journal of biotechnology 0 32884958
2019 Analysis of the amino acid sequences of 18S RNA strains of Babesia canis isolated from dogs, including the analysis of serum proteome of protozoa infected dogs. Annals of parasitology 0 31376344
1996 [Resistance of cytomegalovirus to ganciclovir: rapid detection of the mutations 460 of the UL97 phosphotransferase]. Pathologie-biologie 0 8758494
1993 [A method of competitive dot hydridization for genotyping influenza A viruses]. Voprosy virusologii 0 8284914

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