Affinage

NSA2

Ribosome biogenesis protein NSA2 homolog · UniProt O95478

Length
260 aa
Mass
30.1 kDa
Annotated
2026-06-10
11 papers in source corpus 7 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NSA2 (TINP1) is a conserved nucleolar assembly factor for the large (60S) ribosomal subunit that is required for pre-rRNA maturation and ribosome production (PMID:16861225, PMID:30243719). In yeast, Nsa2 is essential for processing 27SB pre-rRNA and for accumulation of mature 25S and 5.8S rRNA, and human TINP1 functionally complements yeast loss, establishing deep conservation of this role (PMID:16861225). Cryo-EM places Nsa2 on nuclear pre-60S particles through its C-terminal β-barrel, while its extended N-terminus threads between 25S rRNA helices to reach the Nog1 GTPase center; the N-terminus targets Nsa2 to early pre-60S particles, and a conservative Q3N substitution abolishes growth and impairs 60S biogenesis (PMID:33266193). Nsa2 works as a functional partner of the GTPase Nog1, which acts upstream to recruit Nsa2 to pre-60S complexes, and the Nsa2 N-terminus in turn influences Nog1 GTPase recycling on late cytoplasmic particles (PMID:16861225, PMID:33266193). Nsa2 protein levels are coupled to active ribosome assembly, being depleted when upstream biogenesis is blocked (PMID:16861225). In human cells NSA2 localizes to the nucleolus via dual NLS/NoLS signals and drives G1/S progression and cell growth (PMID:19932687), reduces ribosome production and protein synthesis along with mTOR pathway activity upon depletion (PMID:30243719), and promotes proliferation in part through suppression of p53 and p21 (PMID:23912275).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2006 High

    Established NSA2's core molecular function by showing it is required for a specific step of 60S ribosomal subunit biogenesis and that this role is conserved from yeast to human.

    Evidence Yeast genetic depletion with rRNA processing analysis and complementation by human TINP1

    PMID:16861225

    Open questions at the time
    • Did not define the structural basis of pre-60S docking
    • Mechanism by which Nsa2 promotes 27SB cleavage not resolved
  2. 2006 High

    Defined the genetic hierarchy of Nsa2 recruitment by placing the GTPase Nog1 upstream of Nsa2 association with pre-60S particles.

    Evidence Co-purification of pre-ribosomal complexes with reciprocal depletion epistasis in yeast

    PMID:16861225

    Open questions at the time
    • Direct physical contact between Nsa2 and Nog1 not yet visualized at this stage
    • Functional consequence of the Nog1-Nsa2 partnership unresolved
  3. 2006 Medium

    Showed Nsa2 stability is coupled to ongoing ribosome assembly, implying its abundance reports on biogenesis flux.

    Evidence Depletion of upstream biogenesis factors followed by Nsa2 protein-level measurement

    PMID:16861225

    Open questions at the time
    • Degradation pathway and turnover machinery not identified
    • Tested in only two genetic contexts in a single lab
  4. 2009 Medium

    Linked human NSA2 nucleolar targeting to cell cycle control, showing it promotes G1/S progression and growth.

    Evidence GFP-fusion localization with NLS/NoLS mapping, siRNA and overexpression with flow cytometry

    PMID:19932687

    Open questions at the time
    • Whether cell cycle effect is a direct consequence of ribosome biogenesis defect not separated
    • Single lab
  5. 2012 Medium

    Identified a context-dependent cytosolic pool of NSA2 and a TGFβ1-driven nuclear translocation, placing NSA2 upstream of TGFβ1 transcriptional activity in mesangial cells.

    Evidence Immunofluorescence localization, RNAi, TGFβ1 ELISA/RT-PCR and fibronectin mRNA measurement

    PMID:23220173

    Open questions at the time
    • Molecular mechanism connecting NSA2 to TGFβ1 transcription unknown
    • Apparent discrepancy with nucleolar localization in other cell types unresolved
    • Single lab
  6. 2013 Medium

    Connected NSA2-driven proliferation to suppression of the p53/p21 axis.

    Evidence siRNA/overexpression with viability, cell cycle, reporter and p53/p21 protein and mRNA readouts

    PMID:23912275

    Open questions at the time
    • No direct interaction assay placing NSA2 on the p53 pathway
    • Whether p53 suppression is downstream of ribosome biogenesis stress not addressed
  7. 2018 Medium

    Confirmed in human cells that NSA2 supports rRNA synthesis, 60S formation and protein synthesis, and linked its loss to mTOR pathway inactivation.

    Evidence siRNA knockdown with rRNA synthesis, subunit analysis, protein synthesis and mTOR western blot

    PMID:30243719

    Open questions at the time
    • Whether mTOR effect is direct or secondary to translation defect unresolved
    • Single lab
  8. 2020 High

    Provided the structural mechanism of NSA2 action, showing C-terminal β-barrel docking to pre-60S and an N-terminal extension reaching the Nog1 GTPase center that governs targeting and Nog1 recycling.

    Evidence Cryo-EM structure with site-directed mutagenesis (Q3N), growth assays and pre-60S fractionation

    PMID:33266193

    Open questions at the time
    • Exact role in triggering 27SB cleavage not mechanistically defined
    • Structural data from yeast; human-specific features not resolved
  9. 2025 Low

    Proposed an NSA2-EGFR axis that destabilizes wild-type p53 as a druggable vulnerability in NSCLC.

    Evidence Camptothecin derivative 9c treatment with p53 western blot, cell cycle, apoptosis and xenograft readouts

    PMID:40076615

    Open questions at the time
    • No direct NSA2-EGFR binding assay reported; interaction inferred from drug effects
    • Mechanism linking the axis to p53 destabilization not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NSA2's ribosome biogenesis role mechanistically integrates with its reported effects on p53/p21, TGFβ1 and EGFR signaling remains unresolved.
  • No demonstrated physical link between NSA2 and p53 or EGFR
  • Whether signaling phenotypes are secondary to nucleolar/ribosomal stress untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0005198 structural molecule activity 1
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1640170 Cell Cycle 2 R-HSA-8953854 Metabolism of RNA 2
Partners
EGFRNOG1
Complex memberships
pre-60S ribosomal particle

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Yeast Nsa2 is required for maturation of 27SB pre-rRNA and large (60S) ribosomal subunit biogenesis; its absence leads to accumulation of 27SB pre-rRNA and decreased 25S and 5.8S rRNA levels. Human TINP1 (NSA2 ortholog) complements yeast NSA2 repression, confirming functional conservation. Yeast genetic depletion, RNA analysis, complementation with human TINP1 The Journal of biological chemistry High 16861225
2006 Nsa2 is a functional partner of the putative GTPase Nog1 on pre-60S particles: in the absence of Nog1, Nsa2 disappears from pre-60S complexes, but in the absence of Nsa2, Nog1 can still associate with (maturation-blocked) pre-60S complexes. This epistatic relationship places Nog1 upstream of Nsa2 association. Co-purification of pre-ribosomal complexes, genetic depletion epistasis experiments The Journal of biological chemistry High 16861225
2006 Nsa2 is an unstable (short half-life) protein whose cellular levels are tightly regulated: when ribosome biogenesis is blocked upstream of Nsa2, the protein is largely depleted, indicating its stability is coupled to active ribosome assembly. Genetic depletion of upstream ribosome biogenesis factors followed by Nsa2 protein level measurement The Journal of biological chemistry Medium 16861225
2009 Human NSA2 localizes to the nucleolus; both putative nuclear localization signals (NLSs) also function as nucleolar localization signals (NoLSs) and are sufficient to direct nucleolar accumulation. Overexpression promotes G1/S cell cycle progression and cell growth; siRNA knockdown blocks G1/S transition and attenuates growth. GFP-fusion subcellular localization, deletion/mutation of NLS/NoLS, siRNA knockdown and overexpression with flow cytometry cell cycle analysis Biochemical and biophysical research communications Medium 19932687
2013 TINP1 (NSA2) overexpression promotes cell proliferation and S-phase entry while significantly reducing p53 and p21 protein/mRNA levels; TINP1 knockdown reduces cell viability. This places TINP1 upstream of p53/p21 in a proliferation-regulatory pathway. siRNA knockdown, overexpression, CCK-8 viability assay, luciferase reporter, flow cytometry, Western blot/RT-PCR for p53 and p21 Oncology reports Medium 23912275
2012 NSA2 protein is predominantly cytosolic in cultured renal mesangial cells (not nuclear as previously described in other cell types); exogenous TGFβ1 causes NSA2 to translocate from cytosol to nucleus. NSA2 knockdown by RNAi almost abolishes TGFβ1 mRNA/protein and activity and reduces fibronectin mRNA, placing NSA2 upstream of TGFβ1 transcriptional activity. Immunofluorescence subcellular localization, RNA interference, TGFβ1 ELISA/RT-PCR, fibronectin mRNA measurement The international journal of biochemistry & cell biology Medium 23220173
2018 Human NSA2 is required for 60S ribosomal subunit biogenesis and protein synthesis: NSA2 knockdown reduces rRNA synthesis, diminishes the 60S subunit, and suppresses overall protein synthesis. NSA2 depletion also inactivates the mTOR signaling pathway. siRNA knockdown, rRNA synthesis assay, ribosome profiling/subunit analysis, protein synthesis measurement, mTOR pathway western blot Biochemical and biophysical research communications Medium 30243719
2020 Cryo-EM structures show Nsa2 docked via its C-terminal β-barrel domain to nuclear pre-60S particles, with an extended N-terminus (three α-helical segments) meandering between 25S rRNA helices and the extreme N-terminus near the Nog1 GTPase center. A conservative N-terminal mutation (Q3N) abolishes cell growth and impairs 60S biogenesis. The N-terminus is required to target Nsa2 to early pre-60S particles, and overexpression of the N-terminus (residues 1–58) arrests Nog1 on late cytoplasmic pre-60S particles, implicating a functional interaction between the Nsa2 N-terminus and Nog1 GTPase recycling. Cryo-EM structure, site-directed mutagenesis, yeast growth assay, biochemical fractionation of pre-60S particles International journal of molecular sciences High 33266193
2025 NSA2 forms an axis with EGFR that destabilizes wild-type p53: the camptothecin derivative 9c disrupts the NSA2-EGFR interaction, leading to p53 stabilization, cell cycle arrest, and apoptosis in NSCLC cells. Drug treatment with mechanistic follow-up (p53 western blot, cell cycle analysis, apoptosis assay, xenograft in vivo model) International journal of molecular sciences Low 40076615

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Nsa2 is an unstable, conserved factor required for the maturation of 27 SB pre-rRNAs. The Journal of biological chemistry 40 16861225
2009 NSA2, a novel nucleolus protein regulates cell proliferation and cell cycle. Biochemical and biophysical research communications 28 19932687
2013 A novel human TINP1 gene promotes cell proliferation through inhibition of p53 and p21 expression. Oncology reports 8 23912275
2012 Nop-7-associated 2 (NSA2), a candidate gene for diabetic nephropathy, is involved in the TGFβ1 pathway. The international journal of biochemistry & cell biology 7 23220173
2020 Mutational Analysis of the Nsa2 N-Terminus Reveals Its Essential Role in Ribosomal 60S Subunit Assembly. International journal of molecular sciences 6 33266193
2011 Elevated levels of renal and circulating Nop-7-associated 2 (NSA2) in rat and mouse models of diabetes, in mesangial cells in vitro and in patients with diabetic nephropathy. Diabetologia 6 22095236
2018 Nop-7-associated 2 (NSA2) is required for ribosome biogenesis and protein synthesis. Biochemical and biophysical research communications 5 30243719
2022 MiR-601 Promotes Cell Proliferation of Human Glioblastoma Cells by Suppressing TINP1 Expression. Alternative therapies in health and medicine 3 35139491
2019 TINP1 homolog is required for planarian regeneration. Bioscience, biotechnology, and biochemistry 3 30913994
2025 Novel Camptothecin Derivative 9c with Enhanced Antitumor Activity via NSA2-EGFR-P53 Signaling Pathway. International journal of molecular sciences 1 40076615
2024 Co-regulation and synteny of GFM2 and NSA2 links ribosomal function in mitochondria and the cytosol with chronic kidney disease. Molecular medicine (Cambridge, Mass.) 1 39396937

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