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RSL1D1

Ribosomal L1 domain-containing protein 1 · UniProt O76021

Length
490 aa
Mass
55.0 kDa
Annotated
2026-06-10
18 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RSL1D1 (CSIG) is a nucleolar ribosomal L1 domain-containing protein that functions as a multi-modal regulator of proliferation and senescence, acting both as a sequence-specific mRNA-binding protein and as a protein-level modulator of degradation pathways (PMID:18678645, PMID:27811966). As an RNA-binding regulator it suppresses translation of PTEN mRNA by binding its 5' UTR, lowering PTEN and downstream p27(Kip1) to drive proliferation and delay replicative senescence (PMID:18678645), and conversely stabilizes target mRNAs by binding their 3' UTRs: it stabilizes PPARγ mRNA in a HuR-dependent manner (PMID:35940221) and FTH1 (ferritin heavy chain) mRNA, where its loss derepresses iron accumulation and triggers ferroptosis (PMID:36913375). Both its N-terminal ribosomal L1 domain and C-terminal lysine-rich region are individually required for full activity and correct subcellular localization (PMID:26686419). RSL1D1 also acts on the ubiquitin–proteasome system in a context-dependent manner, binding the MDM2 RING domain to inhibit p53 ubiquitination and enable p53-dependent G1 arrest under nucleolar stress (PMID:27811966), yet in colorectal cancer cells recruiting wild-type p53 to HDM2 to enhance its degradation (PMID:35597299), and stabilizing oncogenic c-MYC against proteasomal turnover (PMID:25749381). Additional reported activities include competitive inhibition of Sirt7-mediated RAN deacetylation to restrain STAT3-driven autophagy (PMID:35013134) and a p33ING1-dependent pro-apoptotic role following UV stress (PMID:22419112). Structural work on the yeast ortholog Utp30 defines a two-domain fold that recognizes rRNA duplexes (18S rRNA helix 41 and 5' ETS helix 4) through a concave domain I surface, placing the protein peripherally on small-subunit preribosomes (PMID:28951391).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2008 High

    Established RSL1D1/CSIG's first non-ribosomal function: translational repression of a tumor suppressor to control the senescence/proliferation balance.

    Evidence RIP, PTEN 5' UTR luciferase reporter, knockdown/overexpression with senescence (SA-β-gal) and epistasis in PTEN-null cells

    PMID:18678645

    Open questions at the time
    • Did not define the RNA-binding determinants on RSL1D1 itself
    • Did not address whether the same domain mediates other targets
  2. 2012 Medium

    Linked RSL1D1 to a stress-responsive apoptotic axis, showing its protein stability and pro-apoptotic output depend on a nucleolar partner.

    Evidence Reciprocal Co-IP, immunofluorescence, UV irradiation and BAX-dependent apoptosis readouts with p33ING1 domain mapping

    PMID:22419112

    Open questions at the time
    • Mechanism of CSIG stabilization by p33ING1 unresolved
    • Single lab; no in vivo validation
  3. 2015 Medium

    Extended RSL1D1 beyond RNA regulation to direct protein stabilization, showing it protects oncogenic c-MYC from proteasomal degradation, and dissected its domain requirements.

    Evidence Co-IP, ubiquitination assay, colony formation and xenograft; separate truncation analysis with PTEN/senescence readouts

    PMID:25749381 PMID:26686419

    Open questions at the time
    • Mechanism by which RSL1D1 blocks c-MYC ubiquitination not defined
    • Why isolated NT/CT fragments invert function and mislocalize unexplained
  4. 2016 High

    Resolved how nucleolar stress couples RSL1D1 to p53: relocalization to the nucleoplasm and direct inhibition of MDM2 E3 ligase activity stabilizes p53 and drives G1 arrest.

    Evidence Co-IP mapped to MDM2 RING domain, MDM2-mediated p53 ubiquitination assay, immunofluorescence translocation, cell-cycle readouts

    PMID:27811966

    Open questions at the time
    • Signal triggering nucleolar-to-nucleoplasm translocation not identified
    • Stoichiometry/structure of the RSL1D1–MDM2–p53 complex unknown
  5. 2017 High

    Provided the structural basis for RSL1D1 as an RNA-binding protein, defining a two-domain fold that recognizes rRNA duplexes on small-subunit preribosomes via the yeast ortholog Utp30.

    Evidence X-ray crystallography (2.65 Å), cryo-EM fitting into 90S, RNA-binding analysis, yeast deletion strain composition analysis

    PMID:28951391

    Open questions at the time
    • Whether the concave domain I surface mediates mammalian mRNA-target recognition not tested
    • Functional consequence of peripheral 90S binding in mammals unclear
  6. 2022 Medium

    Revealed context-dependent, opposing roles in p53 control and added mRNA-stabilizing and acetylation-modulating activities, broadening RSL1D1 into a multi-substrate cancer regulator.

    Evidence Co-IP/domain mapping and ubiquitination for p53–HDM2 recruitment; RIP/RNA pulldown/reporter for PPARγ 3' UTR; competitive Co-IP and acetylation/autophagy assays for RAN–Sirt7

    PMID:35013134 PMID:35597299 PMID:35940221

    Open questions at the time
    • How RSL1D1 switches between stabilizing and degrading p53 across cell contexts unresolved
    • Each mechanism rests on single-lab Co-IP evidence without reciprocal cross-validation
  7. 2023 Medium

    Connected RSL1D1's 3' UTR-binding activity to iron homeostasis and ferroptosis, and showed RSL1D1 itself is subject to ubiquitin-mediated turnover in senescent cells.

    Evidence RIP, FTH1 3' UTR binding, knockdown with ferrous iron/MDA/GPX4 readouts, ubiquitination assay for RSL1D1 degradation

    PMID:36913375

    Open questions at the time
    • E3 ligase degrading RSL1D1 not identified
    • How a single protein selects among many 3' UTR targets unknown
  8. 2025 Low

    Added NRF2 to RSL1D1's roster of stabilized proteins, implicating it in oxidative-stress/proliferation control in lung adenocarcinoma.

    Evidence Co-IP and ubiquitination assay with proliferation readouts

    PMID:40543689

    Open questions at the time
    • Single Co-IP plus ubiquitination assay, single lab, limited methods detail
    • Direct binding interface and reciprocal validation absent

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how one nucleolar L1-domain protein selects among such diverse RNA (5'/3' UTR) and protein targets, and what governs its switch between tumor-suppressive (p53 stabilization, ferroptosis promotion) and oncogenic (p53 degradation, c-MYC/NRF2 stabilization) outputs.
  • No unified model linking the conserved RNA-binding fold to target selection
  • Determinants of cell-context-dependent functional polarity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0098772 molecular function regulator activity 4 GO:0045182 translation regulator activity 1
Localization
GO:0005730 nucleolus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1640170 Cell Cycle 1
Partners
HURING1MDM2MYCNFE2L2RANSIRT7TP53

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 CSIG/RSL1D1 binds directly to the 5' UTR of PTEN mRNA and suppresses its translation, thereby reducing PTEN protein levels and downstream p27(Kip1) expression to promote cell proliferation and delay replicative senescence. RNA immunoprecipitation (RIP), luciferase reporter assay (PTEN 5' UTR), knockdown/overexpression with proliferation and senescence readouts (SA-β-gal), genetic epistasis using PTEN-silenced/deficient cells Molecular and cellular biology High 18678645
2012 CSIG/RSL1D1 is a nucleolar protein that interacts with p33ING1; after UV irradiation, p33ING1 translocates to the nucleolus and binds CSIG, stabilizing CSIG protein. This p33ING1–CSIG complex promotes apoptosis via activation of BAX (Bcl-2-associated X protein). Co-immunoprecipitation, immunofluorescence localization, UV irradiation assay, apoptosis readouts, domain-mapping (p33ING1 nucleolar targeting sequence required for CSIG interaction) Cell death & disease Medium 22419112
2015 CSIG/RSL1D1 directly interacts with c-MYC protein and protects it from ubiquitination and proteasomal degradation, thereby increasing c-MYC protein levels and promoting hepatocellular carcinoma cell proliferation. Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression with colony formation and xenograft assays Oncotarget Medium 25749381
2015 Both the N-terminal ribosomal L1 domain and the C-terminal lysine-rich region of CSIG/RSL1D1 are individually necessary but not sufficient for its function; full-length CSIG reduces PTEN expression and promotes proliferation, while truncated fragments (NT or CT alone) fail to alter PTEN levels and instead inhibit proliferation and accelerate senescence. The two truncated fragments also display altered subcellular localization compared to wild-type CSIG. Domain-deletion/truncation expression, western blotting (PTEN levels), SA-β-gal senescence assay, cell proliferation assay, immunofluorescence for subcellular localization Biochemical and biophysical research communications Medium 26686419
2016 CSIG/RSL1D1 translocates from the nucleolus to the nucleoplasm under nucleolar stress, directly binds the MDM2 RING finger domain, and inhibits MDM2 E3 ubiquitin ligase activity, thereby reducing p53 ubiquitination and degradation and enabling p53-dependent G1 arrest. Co-immunoprecipitation (CSIG–MDM2 interaction, mapping to RING finger domain), ubiquitination assay (MDM2-mediated p53 ubiquitination), knockdown with p53 protein level and cell-cycle readouts, immunofluorescence for nucleolar-to-nucleoplasm translocation Scientific reports High 27811966
2017 Crystal structure of yeast Utp30 (ortholog of RSL1D1/Cic1 in small subunit preribosomes) at 2.65 Å resolution reveals a two-domain fold that fits into 90S cryo-EM density; Utp30 binds rearranged helix 41 of 18S rRNA and helix 4 of 5' ETS via its concaved domain I surface. Deletion of Utp30 does not affect 90S composition, consistent with its peripheral location. X-ray crystallography (2.65 Å), cryo-EM fitting, RNA-binding analysis, yeast deletion strain analysis of 90S composition RNA (New York, N.Y.) High 28951391
2022 RSL1D1 directly interacts with the DNA-binding domain (aa 93-292, more precisely aa 93-224) of wild-type p53 and recruits p53 to HDM2, forming an RSL1D1/HDM2/p53 complex that enhances p53 ubiquitination and decreases p53 protein levels in CRC cells. Mutations in p53 (R175H) abolish this interaction, while R273H weakens it, preventing HDM2 recruitment and allowing mutant p53 accumulation. Co-immunoprecipitation, domain-mapping (p53 deletion mutants), ubiquitination assay, western blotting for p53 protein levels Experimental cell research Medium 35597299
2022 RSL1D1 interacts with RAN GTPase and competitively inhibits RAN deacetylation by Sirt7, thereby maintaining RAN in an acetylated state, which inhibits nuclear STAT3 accumulation and STAT3-regulated autophagy, promoting CRC cell proliferation and metastasis. Co-immunoprecipitation (RSL1D1–RAN, RSL1D1–Sirt7 competitive binding), acetylation assay, nuclear fractionation for STAT3, autophagy flux assay, knockdown/overexpression with proliferation and invasion readouts Cell death & disease Medium 35013134
2022 RSL1D1 directly binds the 3' UTR of PPARγ mRNA and stabilizes it in a HuR-dependent manner, increasing PPARγ mRNA and protein levels and thereby regulating downstream targets (PTEN/p27, NF-κB, GLUT4, ACL) to modulate cellular senescence and proliferation. RNA immunoprecipitation (RIP), biotin-labeled RNA pulldown, dual luciferase reporter assay, western blotting, real-time PCR, SA-β-gal staining, cell proliferation and colony formation assays Life sciences Medium 35940221
2023 RSL1D1 directly binds the 3' UTR of FTH1 (ferritin heavy chain 1) mRNA and promotes its stability; RSL1D1 knockdown reduces FTH1 expression, increases transferrin receptor 1, causes intracellular ferrous iron accumulation, and induces ferroptosis (increased MDA, decreased GPX4). RSL1D1 protein is itself downregulated by ubiquitin-mediated proteolysis in senescent CRC cells. RNA immunoprecipitation (RIP), 3'-UTR binding assay, knockdown with iron metabolism readouts (ferrous iron assay, MDA, GPX4 western blot), cell proliferation and apoptosis assays, ubiquitination assay for RSL1D1 degradation Carcinogenesis Medium 36913375
2025 RSL1D1 interacts with NRF2 and inhibits its ubiquitination, thereby preventing NRF2 degradation and promoting lung adenocarcinoma cell proliferation. Co-immunoprecipitation (RSL1D1–NRF2 interaction), ubiquitination assay, knockdown/overexpression with proliferation readouts Gene Low 40543689

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel. Neuron 155 8845168
1994 Genomic organization of the human muscle chloride channel CIC-1 and analysis of novel mutations leading to Becker-type myotonia. Human molecular genetics 113 7951242
1997 Identification of functionally important regions of the muscular chloride channel CIC-1 by analysis of recessive and dominant myotonic mutations. Human molecular genetics 65 9158157
2001 Cic1, an adaptor protein specifically linking the 26S proteasome to its substrate, the SCF component Cdc4. The EMBO journal 42 11500370
2008 CSIG inhibits PTEN translation in replicative senescence. Molecular and cellular biology 41 18678645
1999 Modulation of the gating of CIC-1 by S-(-) 2-(4-chlorophenoxy) propionic acid. British journal of pharmacology 32 10217531
2022 RSL1D1 promotes the progression of colorectal cancer through RAN-mediated autophagy suppression. Cell death & disease 27 35013134
2012 Nucleolar protein CSIG is required for p33ING1 function in UV-induced apoptosis. Cell death & disease 25 22419112
2015 CSIG promotes hepatocellular carcinoma proliferation by activating c-MYC expression. Oncotarget 21 25749381
2016 Regulation of the MDM2-p53 pathway by the nucleolar protein CSIG in response to nucleolar stress. Scientific reports 19 27811966
2004 Expression of novel isoforms of the CIC-1 chloride channel in astrocytic glial cells in vitro. Glia 14 15139012
2023 RSL1D1 knockdown induces ferroptosis and mediates ferrous iron accumulation in senescent cells by inhibiting FTH1 mRNA stability. Carcinogenesis 13 36913375
2015 Ribosomal L1 domain and lysine-rich region are essential for CSIG/ RSL1D1 to regulate proliferation and senescence. Biochemical and biophysical research communications 13 26686419
2006 Novel mutations at carboxyl terminus of CIC-1 channel in myotonia congenita. Acta neurologica Scandinavica 8 16629771
2022 RSL1D1 modulates cell senescence and proliferation via regulation of PPARγ mRNA stability. Life sciences 7 35940221
2022 Mutations in DNA binding domain of p53 impede RSL1D1-p53 interaction to escape from degradation in human colorectal cancer cells. Experimental cell research 6 35597299
2017 Structure and RNA recognition of ribosome assembly factor Utp30. RNA (New York, N.Y.) 2 28951391
2025 RSL1D1 regulates lung adenocarcinoma progression by inhibiting NRF2 ubiquitination. Gene 1 40543689

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