Affinage

LAS1L

Ribosomal biogenesis protein LAS1L · UniProt Q9Y4W2

Length
734 aa
Mass
83.1 kDa
Annotated
2026-06-10
25 papers in source corpus 13 papers cited in narrative 13 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

LAS1L is an essential nucleolar factor that drives maturation of the 60S large ribosomal subunit by catalyzing cleavage of the ITS2 spacer within pre-rRNA, and its depletion blocks 28S rRNA synthesis and triggers p53-dependent G1 arrest (PMID:20647540). It executes this step as the endoribonuclease of a HEPN-domain enzyme: both RφXXXH HEPN motifs and conformational flexibility between the two HEPN domains are required to coordinate RNA in the active site and achieve faithful cleavage (PMID:32220933). LAS1L partners with the NOL9 polynucleotide kinase to form a higher-order endonuclease–kinase complex that cleaves ITS2 and phosphorylates the resulting 5'-hydroxyl product, with a NOL9-encoded nucleolar localization sequence directing the assembled complex into the nucleolus (PMID:23175604, PMID:31288032). LAS1L is integrated into a larger nucleolar complex (the mammalian Rix1/rixosome) with PELP1, TEX10, WDR18, NOL9, and SENP3 that co-fractionates with pre-60S particles, where it is recruited to the PELP1-WDR18-TEX10 scaffold through an interface between the WDR18 C-terminal helix and the LAS1L helical domain (PMID:22190735, PMID:40195365). Two post-translational modification systems govern LAS1L activity and complex behavior: SUMO conjugation balanced by the SENP3 protease controls nucleolar partitioning of the complex and the rate of ribosome formation (PMID:21326211), while the deubiquitinase USP36 stabilizes LAS1L and mediates its SUMOylation at K565, a modification specifically required for ITS2 cleavage but dispensable for complex assembly (PMID:39356143). A de novo LAS1L mutation (p.S477N) causes congenital lethal motor neuron disease through disrupted 60S maturation (PMID:24647030). Beyond ribosome biogenesis, loss of LAS1L produces nucleolar stress that engages a p53-dependent autophagy program, and LAS1L supports tumor growth in breast and lung cancer contexts (PMID:34319761, PMID:33664239).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2010 High

    Established that LAS1L is a nucleolar protein essential for large-subunit ribosome biogenesis, answering whether it has a defined functional role rather than being merely nucleolus-localized.

    Evidence siRNA knockdown with Northern blot rRNA processing assays, flow cytometry, and p53 pathway analysis in human cells

    PMID:20647540

    Open questions at the time
    • Did not define the molecular activity of LAS1L itself
    • Did not identify protein partners or the specific processing step
  2. 2011 High

    Defined the multiprotein context of LAS1L by placing it in a nucleolar complex with PELP1, TEX10, WDR18, NOL9, and SENP3 acting at ITS2 processing, moving from a single protein to a functional module.

    Evidence Reciprocal Co-IP, sucrose gradient fractionation, siRNA knockdown with rRNA processing assays, and immunofluorescence

    PMID:22190735

    Open questions at the time
    • Did not assign catalytic roles to individual subunits
    • Mechanism of nucleolar recruitment not resolved at the structural level
  3. 2011 High

    Showed that SUMO conjugation/deconjugation controlled by SENP3 governs nucleolar partitioning of the LAS1L-containing complex, explaining how ribosome formation rate is regulated.

    Evidence Biochemical purification, SUMO modification assays, SENP3 depletion, and subcellular fractionation

    PMID:21326211

    Open questions at the time
    • SUMO acceptor site on LAS1L not mapped here
    • Causal link between SUMO state and catalytic step not established
  4. 2012 High

    Yeast ortholog work revealed that Las1 associates with pre-60S particles and the Grc3 polynucleotide kinase, whose kinase activity is needed for ITS2 processing, establishing the conserved endonuclease-kinase partnership.

    Evidence Co-IP, sucrose gradient sedimentation, Northern blot, and kinase-dead Grc3 mutant analysis in S. cerevisiae

    PMID:23175604

    Open questions at the time
    • Did not demonstrate LAS1L's own nuclease activity directly
    • Catalytic mechanism of cleavage unresolved
  5. 2012 Medium

    Identified the same subunits as the 5FMC complex recruited to arginine-methylated CHTOP, with PELP1 as the stabilizing scaffold, broadening the complex's role beyond rRNA processing to methylation-linked desumoylation.

    Evidence Biotinylation-proteomics pulldown, Co-IP, knockdown stability assays, and sumoylation assays

    PMID:22872859

    Open questions at the time
    • Single-lab proteomics, the CHTOP link not independently validated
    • Direct role of LAS1L in this function not isolated
  6. 2014 Medium

    Linked LAS1L to human disease by showing a de novo p.S477N mutation causes congenital lethal motor neuron disease via impaired 60S maturation.

    Evidence Exome sequencing plus zebrafish morpholino knockdown with wild-type vs. mutant RNA rescue

    PMID:24647030

    Open questions at the time
    • Single family/single lab
    • Molecular effect of S477N on catalysis or complex assembly not defined
  7. 2019 High

    Reconstituted the human LAS1L-NOL9 endonuclease-kinase complex and showed a NOL9-encoded NoLS directs its nucleolar transport, defining the spatial logic of late pre-rRNA processing.

    Evidence Co-IP, deletion mapping of the NoLS, high-resolution fluorescence imaging, and rRNA processing assays

    PMID:31288032

    Open questions at the time
    • Atomic structure of the active site not yet determined
    • How the complex docks onto pre-60S not resolved
  8. 2020 High

    Defined LAS1L's catalytic mechanism by showing both HEPN motifs and inter-domain flexibility are required for faithful RNA cleavage, identifying it as the endoribonuclease.

    Evidence In vitro endoribonuclease assays, systematic active-site mutagenesis, HEPN chimera reconstitution, and yeast complementation

    PMID:32220933

    Open questions at the time
    • Mostly yeast/orthologous system
    • Precise RNA substrate recognition determinants not fully mapped
  9. 2021 Medium

    Placed LAS1L in a nucleolar stress–p53–autophagy axis, showing its loss drives metabolic remodeling and autophagy rather than apoptosis in tumor cells.

    Evidence siRNA knockdown, RNA Pol I inhibition (CX-5461), gene expression and autophagy assays in solid tumor lines

    PMID:34319761

    Open questions at the time
    • Single lab
    • Mechanism distinguishing autophagy from apoptosis downstream of p53 not detailed
  10. 2021 Medium

    Connected LAS1L to oncogenic signaling by showing it is elevated in TNBC downstream of β-catenin and supports tumor growth and invasion.

    Evidence Nucleolar proteomics, β-catenin inhibitor treatment, xenograft growth and invasion assays

    PMID:33664239

    Open questions at the time
    • Single lab
    • Whether the tumor phenotype reflects ribosome biogenesis or a separate activity not resolved
  11. 2022 Medium

    Identified hnRNPA1 as a direct regulator of LAS1L alternative splicing, showing it binds intronic sites to control exon 9 inclusion and the LAS1L-L/S isoform ratio in cancer.

    Evidence RNA immunoprecipitation, RNA pulldown, splicing assays, and Transwell migration/invasion assays in lung cancer cells

    PMID:35814393

    Open questions at the time
    • Single lab
    • Functional difference between LAS1L-L and LAS1L-S isoforms in ribosome biogenesis not established
  12. 2024 High

    Resolved a regulatory mechanism by showing USP36 stabilizes LAS1L and mediates K565 SUMOylation specifically required for ITS2 cleavage, decoupling this modification from complex assembly.

    Evidence Co-IP, ubiquitination/SUMOylation assays, K565R mutagenesis, and ITS2 processing rescue with WT vs. mutant re-expression

    PMID:39356143

    Open questions at the time
    • How K565 SUMOylation alters catalysis mechanistically not shown
    • Single lab
  13. 2025 High

    Provided the structural basis for rixosome assembly, showing LAS1L is recruited via the WDR18 C-terminal helix contacting its helical domain, explaining how the endonuclease is integrated into the scaffold.

    Evidence Cryo-EM of PELP1-WDR18-TEX10 and LAS1L-NOL9, plus mutagenesis of interface residues and binding assays

    PMID:40195365

    Open questions at the time
    • Full assembled rixosome with bound pre-60S not captured
    • Conformational coupling between scaffold binding and catalysis unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LAS1L catalysis is conformationally coupled to scaffold recruitment, SUMOylation state, and pre-60S substrate engagement within the intact nucleolar particle remains unresolved.
  • No structure of the complete rixosome bound to pre-rRNA substrate
  • Mechanistic link between K565 SUMOylation and HEPN active-site activity not defined
  • Functional distinction between LAS1L splice isoforms unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0003723 RNA binding 2 GO:0016787 hydrolase activity 2
Localization
GO:0005730 nucleolus 3
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9612973 Autophagy 1
Partners
CHTOPHNRNPA1NOL9PELP1SENP3TEX10USP36WDR18
Complex memberships
5FMC complexLAS1L-NOL9 endonuclease-kinase complexrixosome (mammalian Rix1 complex)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 LAS1L is a nucleolar protein required for ribosome biogenesis; depletion of LAS1L inhibits rRNA processing, blocks synthesis of mature 28S rRNA, and causes p53-dependent G1 cell cycle arrest, establishing its essential role in 60S ribosomal subunit biogenesis. siRNA knockdown, rRNA processing assays (Northern blot), flow cytometry, p53 pathway analysis Molecular and cellular biology High 20647540
2011 LAS1L forms a novel nucleolar complex with PELP1, TEX10, WDR18 (mammalian Rix1 complex), NOL9, and SENP3 that co-fractionates with the 60S preribosomal subunit; depletion of complex members causes defects in ITS2 pre-rRNA processing and p53-dependent G1 arrest; nucleolar localization of this complex requires active RNA Pol I transcription and SENP3. Co-immunoprecipitation, sucrose gradient fractionation, siRNA knockdown, rRNA processing assays, immunofluorescence Molecular biology of the cell High 22190735
2011 LAS1L and PELP1 are SUMO targets sensitive to the SUMO-specific protease SENP3; balanced SUMO conjugation/deconjugation controls the nucleolar partitioning of the PELP1-TEX10-WDR18-LAS1L complex, thereby coordinating the rate of ribosome formation and nucleolar release of the large ribosomal subunit. Biochemical purification, SUMO modification assays, SENP3 depletion, subcellular fractionation, Co-IP The EMBO journal High 21326211
2012 In S. cerevisiae, Las1 (ortholog of LAS1L) co-precipitates with 27S rRNA and associates with Nsa1/Rix1-containing pre-60S particles; Las1 interacts with Grc3 polynucleotide kinase, and the kinase activity of Grc3 is required for efficient ITS2 pre-rRNA processing; depletion of Las1 causes accumulation of 27S and 7S rRNA intermediates and impairs 60S subunit synthesis. Co-immunoprecipitation, sucrose gradient sedimentation, Northern blot, kinase-dead Grc3 mutant analysis, yeast genetics Nucleic acids research High 23175604
2012 LAS1L is a component of the Five Friends of Methylated CHTOP (5FMC) nuclear complex, consisting of PELP1, SENP3, WDR18, TEX10, and LAS1L; PELP1 functions as the core scaffold, as other components (including LAS1L) become unstable in its absence; the complex is recruited to CHTOP only when CHTOP is arginine-methylated by PRMT1, linking arginine methylation to desumoylation of transcriptional targets. Biotinylation-proteomics pulldown, Co-IP, siRNA knockdown stability assays, sumoylation assays Molecular & cellular proteomics : MCP Medium 22872859
2014 A de novo mutation in LAS1L (p.S477N) causes congenital lethal motor neuron disease; morpholino knockdown of las1l in zebrafish causes early lethality and disruption of muscle and peripheral nerve architecture, partially rescued by wild-type but not mutant human LAS1L RNA, confirming that disruption of 60S ribosomal subunit maturation is the pathogenic mechanism. Exome sequencing, zebrafish morpholino knockdown, RNA rescue experiment Neurology Medium 24647030
2019 Human LAS1L and NOL9 form a higher-order endonuclease-kinase complex that catalyzes ITS2 pre-rRNA cleavage and 5'-hydroxyl phosphorylation; a Nol9-encoded nucleolar localization sequence (NoLS) is required for nucleolar transport of the assembled Las1L-Nol9 complex; structural analysis by high-resolution imaging defines their spatial organization within the nucleolar sub-structure linked to late pre-rRNA processing. Co-immunoprecipitation, deletion mapping of NoLS, high-resolution fluorescence imaging, functional rRNA processing assays Journal of molecular biology High 31288032
2020 Las1 possesses HEPN endoribonuclease domains; both HEPN nuclease motifs (RφXXXH) are required for nuclease activity and fidelity; systematic mutagenesis of individual HEPN motif residues and reconstituted HEPN-HEPN' chimeras showed that both motifs contribute to coordinating RNA in the active site; conformational flexibility between the two HEPN domains is required for proper RNA cleavage. In vitro endoribonuclease assays, systematic mutagenesis of active-site residues, HEPN chimera reconstitution, in vivo yeast complementation assays The Journal of biological chemistry High 32220933
2021 Depletion of LAS1L (along with PELP1 and NOP2) or inhibition of RNA Pol I induces nucleolar stress that triggers p53-dependent transcriptional programming promoting metabolic remodeling and autophagy (rather than apoptosis) in solid tumor cell lines; blocking autophagy sensitizes cancer cells to RNA Pol I inhibition, placing LAS1L in the nucleolar stress–p53–autophagy axis. siRNA knockdown, RNA Pol I inhibitor (CX-5461), gene expression analysis, autophagy assays, cell death/cell cycle assays Molecular biology of the cell Medium 34319761
2021 LAS1L protein expression is elevated in triple-negative breast cancer (TNBC); β-catenin inhibition decreases LAS1L abundance in the nucleolus; LAS1L functionally enables mammary tumor growth in xenograft models and invasive attributes of TNBC cells, placing LAS1L downstream of β-catenin signaling in TNBC. Nucleolar proteomics, β-catenin inhibitor treatment, xenograft tumor growth assays, invasion assays Cell death & disease Medium 33664239
2022 hnRNPA1 directly binds two specific intronic sites (UAGGGU and UGGGGU) of LAS1L pre-mRNA to inhibit splicing of LAS1L exon 9; knockdown of hnRNPA1 shifts the LAS1L-L/LAS1L-S isoform ratio and promotes migration, invasion, and EMT in lung cancer cells, establishing hnRNPA1 as a regulator of LAS1L alternative splicing. RNA immunoprecipitation (RIP), RNA pulldown, AGE splicing assays, Transwell migration/invasion assays Frontiers in oncology Medium 35814393
2024 The nucleolar deubiquitinase USP36 interacts with both LAS1L and NOL9, stabilizes them via deubiquitination, and mediates SUMOylation of LAS1L at lysine 565 (K565); the K565R mutation abolishes LAS1L function in ITS2 pre-rRNA processing without affecting LAS1L stability or Las1L-Nol9 complex formation, demonstrating that USP36-mediated LAS1L SUMOylation is specifically required for ITS2 cleavage. Co-immunoprecipitation, ubiquitination/SUMOylation assays, site-directed mutagenesis (K565R), ITS2 processing rescue assays (knockdown + re-expression of WT vs. mutant) Cancer research communications High 39356143
2025 Cryo-EM structures of human PELP1-WDR18-TEX10 and LAS1L-NOL9 complexes, plus a lower-resolution model of PELP1-WDR18-LAS1L, reveal that LAS1L is recruited to the rixosome core scaffold (PELP1-WDR18-TEX10-LAS1L) via an interaction between the C-terminal helix of WDR18 and the helical domain of LAS1L; truncation of the WDR18 C-terminal helix abolishes LAS1L binding; TEX10 contacts WDR18 at two separate regions, both required for binding. Cryo-EM structure determination, mutagenesis (truncation and point mutations of WDR18-TEX10 interfaces), biochemical binding assays Nature communications High 40195365

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Molecular psychiatry 248 25644381
2011 The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. The EMBO journal 110 21326211
2011 LAS1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis. Molecular biology of the cell 89 22190735
2010 Las1L is a nucleolar protein required for cell proliferation and ribosome biogenesis. Molecular and cellular biology 56 20647540
2010 Involvement of the tubulin tyrosine ligase-like family member 4 polyglutamylase in PELP1 polyglutamylation and chromatin remodeling in pancreatic cancer cells. Cancer research 51 20442285
2012 Five friends of methylated chromatin target of protein-arginine-methyltransferase[prmt]-1 (chtop), a complex linking arginine methylation to desumoylation. Molecular & cellular proteomics : MCP 49 22872859
2020 Circ_LAS1L regulates cardiac fibroblast activation, growth, and migration through miR-125b/SFRP5 pathway. Cell biochemistry and function 48 31950540
2014 Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis. Neurology 48 24647030
2012 Las1 interacts with Grc3 polynucleotide kinase and is required for ribosome synthesis in Saccharomyces cerevisiae. Nucleic acids research 41 23175604
2021 p53 induces a survival transcriptional response after nucleolar stress. Molecular biology of the cell 25 34319761
2011 Integrative genomic, transcriptomic, and RNAi analysis indicates a potential oncogenic role for FAM110B in castration-resistant prostate cancer. The Prostate 25 21919029
2016 Contextual fear conditioning induces differential alternative splicing. Neurobiology of learning and memory 22 27451143
2020 Genetic landscape of autism spectrum disorder in Vietnamese children. Scientific reports 21 32193494
2021 Inhibiting β-catenin disables nucleolar functions in triple-negative breast cancer. Cell death & disease 18 33664239
2021 New genes involved in Angelman syndrome-like: Expanding the genetic spectrum. PloS one 17 34653234
2020 It takes two (Las1 HEPN endoribonuclease domains) to cut RNA correctly. The Journal of biological chemistry 16 32220933
2015 Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities? American journal of medical genetics. Part A 14 26358559
2019 Nol9 Is a Spatial Regulator for the Human ITS2 Pre-rRNA Endonuclease-Kinase Complex. Journal of molecular biology 13 31288032
2021 A worldwide map of swine short tandem repeats and their associations with evolutionary and environmental adaptations. Genetics, selection, evolution : GSE 11 33892623
2022 Knockdown of hnRNPA1 Promotes NSCLC Metastasis and EMT by Regulating Alternative Splicing of LAS1L exon 9. Frontiers in oncology 9 35814393
2023 Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34. Breast cancer research and treatment 6 37199805
2024 USP36 SUMOylates Las1L and Promotes Its Function in Pre-Ribosomal RNA ITS2 Processing. Cancer research communications 4 39356143
2025 Molecular insights into the overall architecture of human rixosome. Nature communications 3 40195365
2022 Severe Infantile Axonal Neuropathy with Respiratory Failure Caused by Novel Mutation in X-Linked LAS1L Gene. Genes 2 35627110
2018 Pericentromeric regions of homozygosity on the X chromosome: Another likely benign population variant. European journal of medical genetics 0 29572065

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