Affinage

GINS4

DNA replication complex GINS protein SLD5 · UniProt Q9BRT9

Length
223 aa
Mass
26.0 kDa
Annotated
2026-06-10
20 papers in source corpus 16 papers cited in narrative 16 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

GINS4/SLD5 is a core subunit of the heterotetrameric GINS complex, identified through its direct binding to PSF1/GINS1, and functions in the CMG replicative helicase to drive DNA replication and maintain genomic integrity (PMID:16338220, PMID:20709026). Its replication role is essential in vivo: targeted disruption in mice abolishes inner cell mass proliferation and causes peri-implantation lethality (PMID:24244394), and in humans partial loss-of-function compound heterozygous mutations that impair GINS complex assembly delay cell cycle progression and produce a cell-intrinsic block in NK cell and neutrophil development (PMID:36345943). At the mechanistic level of replication initiation, GINS4 recruits the kinase SIK1 to replication sites at S-phase onset, where SIK1 phosphorylates MCM2 at conserved N-terminal residues to activate the MCM helicase (PMID:27592030), and GINS4 also engages the DNA polymerase epsilon subunit POLE2 to sustain proliferation (PMID:40081544). Beyond the replisome, GINS4 localizes to centrosomes and maintains clustering of centriolar satellites, supporting dynein-dependent recruitment of pericentrin, PLK1, Aurora A, and other maturation factors so that spindle poles resist microtubule-based traction forces; its loss disperses satellites and produces fragmented or multipolar spindle poles independently of DNA damage (PMID:29061732). GINS4 additionally functions as a pro-tumorigenic and pro-inflammatory effector: it directly binds and activates the GTPases Rac1 and CDC42 to drive cancer cell growth and metastasis (PMID:31754397), destabilizes p53 via Snail-mediated antagonism of K351 acetylation to suppress ferroptosis (PMID:37018198), and binds the p65 NF-κB subunit to promote its phosphorylation and acetylation and downstream inflammatory cytokine production (PMID:41144169). GINS4 is also a target hijacked by RNA virus matrix proteins (influenza M1, VSV, SeV, HIV) that exploit it to enforce host G0/G1 arrest, and GINS4 itself restrains viral replication and enhances type I interferon signaling (PMID:31050118, PMID:34882534).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2005 Medium

    Established GINS4/SLD5 as a bona fide subunit of the mammalian GINS complex by defining its direct partner, answering whether the SLD5 ortholog physically integrates into the replication machinery.

    Evidence Yeast two-hybrid and immunofluorescence co-localization with PSF1/GINS1

    PMID:16338220

    Open questions at the time
    • Interaction stoichiometry within the full GINS tetramer not resolved
    • No demonstration of replicative function from this binding alone
  2. 2010 Medium

    Tied SLD5 to GINS/CMG assembly and genomic stability in a multicellular organism, showing its loss perturbs cell cycle progression.

    Evidence Co-IP with Psf1, Psf2, Mcm10 plus genetic loss-of-function and cell cycle analysis in Drosophila

    PMID:20709026

    Open questions at the time
    • Mechanistic step within helicase loading/activation not isolated
    • Drosophila phenotype not yet mapped to mammalian requirements
  3. 2013 High

    Demonstrated that SLD5 is essential for proliferation and embryogenesis in vivo, elevating it from a complex component to an organismally required gene.

    Evidence Mouse knockout with histological analysis showing peri-implantation lethality

    PMID:24244394

    Open questions at the time
    • Tissue-specific requirements not dissected
    • Does not distinguish replication from non-replication functions in lethality
  4. 2014 Medium

    Revealed a protective role against DNA damage and a differential repair requirement between normal and cancer cells, hinting at therapeutic selectivity.

    Evidence siRNA knockdown with DNA damage and cell cycle assays across normal and cancer cells

    PMID:25334017

    Open questions at the time
    • Molecular basis of the normal-vs-cancer repair difference unexplained
    • Single-lab observation
  5. 2016 High

    Defined a specific molecular function in replication initiation: GINS4 acts as a recruitment platform for a kinase that activates the MCM helicase.

    Evidence Co-IP, in vitro kinase assay defining five MCM2 phospho-sites, ChIP, and knockdown

    PMID:27592030

    Open questions at the time
    • Structural basis of GINS4-SIK1 binding unknown
    • Whether SIK1 recruitment is conserved across cell types untested
  6. 2017 High

    Uncovered a replication-independent role at centrosomes, showing GINS4 maintains centriolar satellites and spindle-pole integrity against microtubule traction forces.

    Evidence siRNA knockdown, immunofluorescence, live-cell imaging, and HSET co-depletion epistasis

    PMID:29061732

    Open questions at the time
    • Molecular mechanism linking GINS4 to satellite clustering not defined
    • Whether centrosomal pool is distinct from replisome pool unclear
  7. 2019 High

    Identified an oncogenic signaling output, showing GINS4 directly activates Rho-family GTPases to drive cancer growth and metastasis beyond its replication role.

    Evidence Co-IP, GST pull-down, and GTPase activation assays in gastric cancer cells

    PMID:31754397

    Open questions at the time
    • How a replisome subunit accesses cytoplasmic GTPases not explained
    • Direct vs indirect GTPase activation mechanism not resolved
  8. 2019 Medium

    Placed GINS4 under post-transcriptional control, showing LSH stabilizes its mRNA to elevate protein levels in cancer.

    Evidence RNA immunoprecipitation, Co-IP, and rescue experiments in lung cancer

    PMID:31253190

    Open questions at the time
    • Other regulators of GINS4 transcript stability unknown
    • Single-lab finding
  9. 2019 High

    Established GINS4 as a host target of viral matrix proteins, linking its replication function to virus-imposed cell cycle arrest and antiviral resistance.

    Evidence Yeast two-hybrid, Co-IP, cell cycle analysis, and SLD5 transgenic mouse rescue with influenza M1

    PMID:31050118

    Open questions at the time
    • Region of GINS4 bound by M1 not mapped
    • Mechanism by which M1 binding blocks cycle progression unresolved
  10. 2021 Medium

    Generalized the viral-hijack model across multiple RNA viruses and showed GINS4 actively restrains viral replication while boosting interferon signaling.

    Evidence Co-IP, viral replication and interferon assays with VSV, SeV, HIV matrix proteins, in vitro and in vivo

    PMID:34882534

    Open questions at the time
    • Mechanism connecting GINS4 to type I interferon induction not defined
    • Direct vs indirect suppression of viral replication unclear
  11. 2022 High

    Provided human-genetic validation that GINS4 assembly defects cause an immunodeficiency, tying replication competence to NK cell and neutrophil development.

    Evidence Exome sequencing of patients, GINS complex assembly assays, knockdown, and in vitro NK differentiation

    PMID:36345943

    Open questions at the time
    • Why NK/neutrophil lineages are selectively vulnerable not explained
    • Replication-stress-independent mechanism of the developmental block unresolved
  12. 2023 High

    Linked GINS4 to ferroptosis resistance via a p53-destabilizing axis, defining a tumor-survival mechanism distinct from replication.

    Evidence CRISPR/Cas9 knockout, p53 K351 acetylation and mutagenesis assays, and ferroptosis assays in lung adenocarcinoma

    PMID:37018198

    Open questions at the time
    • How GINS4 activates Snail not defined
    • Whether the centrosomal/replisome pool mediates this function unknown
  13. 2025 Medium

    Connected GINS4 to a proliferative kinase pathway through POLE2, coupling replication machinery to PI3K/AKT signaling and ferroptosis control.

    Evidence Computationally predicted interaction confirmed by immunofluorescence, knockdown, rescue, and xenograft in HCC

    PMID:40081544

    Open questions at the time
    • Direct GINS4-POLE2 binding rests on prediction plus colocalization, not biochemical reconstitution
    • Mechanism linking POLE2 to PI3K/AKT not resolved
  14. 2025 Medium

    Extended GINS4 into inflammatory signaling, showing it engages p65 NF-κB to drive cytokine production and lung pathology.

    Evidence Co-IP with p65, phospho/acetylation western blots, and a neonatal rat BPD model

    PMID:41144169

    Open questions at the time
    • Single study with single-lab support
    • How GINS4 promotes p65 modification mechanistically unknown
  15. 2025 Low

    Identified an upstream inducer of GINS4 expression, linking nicotine receptor signaling to GINS4-driven tumor phenotypes.

    Evidence CHRNA5 knockdown, western blot, and proliferation/migration assays with xenograft in LUAD

    PMID:41192616

    Open questions at the time
    • STAT3 pathway placement inferred without direct mechanistic reconstitution
    • Single-lab, low-confidence finding
  16. 2026 Medium

    Refined the centrosomal mechanism by placing GINS4 upstream of dynein-dependent centrosome maturation independently of DNA damage.

    Evidence siRNA knockdown, co-depletion epistasis, ciliobrevin D pharmacological phenocopy, and immunofluorescence (preprint)

    PMID:42182163

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Molecular link between GINS4 and dynein heavy chain expression undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single core replisome subunit physically partitions among its distinct roles at the replication fork, centrosome, cytoplasmic GTPases, and transcription/inflammatory effectors.
  • No structural model distinguishing replisome from moonlighting interactions
  • Whether moonlighting functions require GINS complex assembly untested
  • Mechanism of subcellular targeting between nucleus, centrosome, and cytoplasm unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005815 microtubule organizing center 2 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-168256 Immune System 3 R-HSA-69306 DNA Replication 3 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CDC42MCM10POLE2PSF1RAC1RELASIK1
Complex memberships
CMG helicaseGINS complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 GINS4/SLD5 was identified as a direct binding partner of PSF1 (GINS1), interacting with a central region of PSF1, and co-localizes with PSF1 when overexpressed, establishing SLD5 as a component of the mammalian GINS complex. Yeast two-hybrid, co-localization by immunofluorescence Biochemical and biophysical research communications Medium 16338220
2010 Drosophila Sld5 (ortholog of GINS4) interacts with Psf1, Psf2, and Mcm10 within the GINS/CMG complex, and loss-of-function mutations in Sld5 cause M and S phase delays with chromosomal instability, establishing its essential role in DNA replication and genomic integrity in a multicellular organism. Co-immunoprecipitation, genetic loss-of-function (mutant analysis), cell cycle analysis Biochemical and biophysical research communications Medium 20709026
2013 Targeted disruption of SLD5 in mice causes defective cell proliferation in the inner cell mass and embryonic lethality at the peri-implantation stage, demonstrating SLD5 is essential for early embryogenesis and cell proliferation in vivo. Gene knockout in mice, histological analysis PloS one High 24244394
2014 Attenuation of SLD5 expression induces DNA damage in both normal and cancer cells; however, delay in DNA repair response and cell cycle restoration following SLD5 knockdown occurs in normal cells but NOT in cancer cells, indicating SLD5 protects against DNA damage and is differentially required for repair in normal vs. cancer cells. siRNA knockdown, DNA damage assays, cell cycle analysis PloS one Medium 25334017
2016 GINS4/Sld5 directly interacts with SIK1 (salt-inducible kinase 1) and recruits SIK1 to sites of DNA replication at the onset of S phase; SIK1 then phosphorylates MCM2 at five conserved N-terminal residues, which is essential for MCM helicase activation during DNA replication. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, chromatin immunoprecipitation Cellular signalling High 27592030
2017 Sld5/GINS4 localizes to centrosomes and is required to maintain centriolar satellites clustered around centrosomes; depletion of Sld5 disperses centriolar satellites throughout the cytoplasm, impairs recruitment of pericentrin to centrosomes, and renders centrosomes unable to resist CENP-E- and Kid-mediated microtubular forces during chromosome congression, leading to monocentriolar and acentriolar spindle poles. HSET (kinesin-14) sustains the traction forces mediating centrosomal fragmentation in Sld5-depleted cells. siRNA knockdown, immunofluorescence/localization, live-cell imaging, genetic epistasis (co-depletion) Molecular and cellular biology High 29061732
2019 GINS4 directly binds to Rac1 and CDC42 (demonstrated by Co-IP and GST pull-down), activating these GTPases and their downstream pathways, thereby promoting gastric cancer cell growth and metastasis. Co-immunoprecipitation, GST pull-down, GTPase activation assays, cDNA array Theranostics High 31754397
2019 LSH (lymphoid-specific helicase) binds to the 3'UTR region of GINS4 mRNA and stabilizes its transcript levels (demonstrated by Co-IP and RNA immunoprecipitation), thereby increasing GINS4 protein expression and promoting lung cancer progression. Co-immunoprecipitation, RNA immunoprecipitation (RIP), western blot, rescue experiments Journal of experimental & clinical cancer research Medium 31253190
2019 Influenza virus matrix protein M1 directly interacts with SLD5/GINS4 (identified by yeast two-hybrid, confirmed in mammalian cells); this interaction mediates M1-induced host cell cycle blockade at G0/G1 phase. Overexpression of SLD5 partially rescues M1-induced G0/G1 arrest, and SLD5 transgenic mice show higher resistance to influenza infection. Yeast two-hybrid, co-immunoprecipitation, cell cycle analysis, transgenic mouse model, rescue experiments Cellular microbiology High 31050118
2021 Matrix proteins of multiple RNA viruses (VSV, SeV, HIV) interact with SLD5/GINS4 and induce G0/G1 cell cycle arrest; overexpression of SLD5 partially rescues this arrest and SLD5 suppresses VSV replication in vitro and in vivo while enhancing type I interferon signaling. Co-immunoprecipitation, cell cycle analysis, viral replication assays, in vivo experiments, interferon signaling assays The Journal of general virology Medium 34882534
2022 Partial loss-of-function compound heterozygous mutations in GINS4 impair expression and assembly of the GINS complex, causing delayed cell cycle progression without increased replication stress. GINS4 knockdown in differentiating NK cells in vitro demonstrates a cell-intrinsic defect in NK cell development, establishing GINS4 as necessary for NK cell and neutrophil development. Exome sequencing, patient-derived cell analysis, GINS4 knockdown, cell cycle analysis, in vitro NK cell differentiation assay JCI insight High 36345943
2023 GINS4 suppresses p53 stability by activating Snail, which antagonizes acetylation of p53 at lysine residue K351; this destabilization of p53 inhibits ferroptosis. CRISPR/Cas9-mediated GINS4 knockout facilitates ferroptosis in lung adenocarcinoma cells, particularly in G2/M cells. CRISPR/Cas9 knockout, ferroptosis assays, Co-immunoprecipitation, p53 acetylation assays, site-directed mutagenesis (K351) Proceedings of the National Academy of Sciences of the United States of America High 37018198
2025 GINS4 directly interacts with POLE2 (DNA polymerase epsilon subunit 2); GINS4 silencing inhibits POLE2 expression, leading to suppression of PI3K/AKT signaling, reduced HCC cell proliferation and cell cycle progression, and promotion of ferroptosis. POLE2 overexpression reverses the effects of GINS4 knockdown. Co-immunoprecipitation (predicted by STRING/HDOCK, confirmed by immunofluorescence), siRNA knockdown, rescue overexpression, western blot for PI3K/AKT pathway, ferroptosis assays, in vivo xenograft Cellular signalling Medium 40081544
2025 GINS4 directly interacts with p65 NF-κB subunit and promotes phosphorylation and acetylation of p65, thereby driving NF-κB-mediated inflammatory cytokine production (IL-6, IL-1β, IL-18, IFN-γ, TNF-α) and BPD-like pathological changes in lung tissue. Co-immunoprecipitation (direct interaction with p65), western blot for phosphorylation/acetylation, in vivo neonatal rat model, histological analysis Molecular biotechnology Medium 41144169
2025 α5-nAChR mediates nicotine-induced GINS4 expression via STAT3 signaling, linking nicotine receptor activation to GINS4-driven LUAD cell proliferation, migration, and invasion. siRNA knockdown (CHRNA5), western blot, in vitro proliferation/migration assays, xenograft model Food and chemical toxicology Low 41192616
2026 Sld5/GINS4 depletion in cancer cells disperses PCM1-, AZI1-, and CEP290-positive centriolar satellites, reduces dynein heavy chain expression, and destabilizes dynein-dynactin localization at spindle poles, impairing recruitment of PLK1, Aurora A, CEP192, and CEP215 to centrosomes and causing multipolar spindle formation. Direct dynein depletion or pharmacological inhibition (ciliobrevin D) phenocopies Sld5 loss, placing SLD5 upstream of dynein-dependent centrosome maturation. These defects occur without detectable DNA damage. siRNA knockdown, co-depletion epistasis, pharmacological inhibition (ciliobrevin D), immunofluorescence localization, western blot bioRxivpreprint Medium 42182163

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42. Theranostics 66 31754397
2023 GINS4 suppresses ferroptosis by antagonizing p53 acetylation with Snail. Proceedings of the National Academy of Sciences of the United States of America 47 37018198
2019 LSH interacts with and stabilizes GINS4 transcript that promotes tumourigenesis in non-small cell lung cancer. Journal of experimental & clinical cancer research : CR 44 31253190
2022 Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia. JCI insight 20 36345943
2010 Drosophila Sld5 is essential for normal cell cycle progression and maintenance of genomic integrity. Biochemical and biophysical research communications 19 20709026
2016 GINS complex protein Sld5 recruits SIK1 to activate MCM helicase during DNA replication. Cellular signalling 17 27592030
2013 Requirement of SLD5 for early embryogenesis. PloS one 16 24244394
2019 Influenza virus matrix protein M1 interacts with SLD5 to block host cell cycle. Cellular microbiology 14 31050118
2005 Identification and characterization of mouse PSF1-binding protein, SLD5. Biochemical and biophysical research communications 13 16338220
2023 The Molecular Pathogenesis of Tumor-Suppressive miR-486-5p and miR-486-3p Target Genes: GINS4 Facilitates Aggressiveness in Lung Adenocarcinoma. Cells 10 37508549
2018 Visualization of Proliferative Vascular Endothelial Cells in Tumors in Vivo by Imaging Their Partner of Sld5-1 Promoter Activity. The American journal of pathology 8 29650228
2022 Hsa_circ_0008673 Promotes Breast Cancer Progression by MiR-578/GINS4 Axis. Clinical breast cancer 7 36628810
2017 Sld5 Ensures Centrosomal Resistance to Congression Forces by Preserving Centriolar Satellites. Molecular and cellular biology 6 29061732
2014 DNA damage enhanced by the attenuation of SLD5 delays cell cycle restoration in normal cells but not in cancer cells. PloS one 6 25334017
2025 GINS4 silencing mediates hepatocellular cancer cell proliferation, cycle and ferroptosis through POLE2. Cellular signalling 3 40081544
2021 Multiple RNA virus matrix proteins interact with SLD5 to manipulate host cell cycle. The Journal of general virology 3 34882534
2022 MicroRNA-133a-3p Inhibits Lung Adenocarcinoma Development and Cisplatin Resistance through Targeting GINS4. Cells, tissues, organs 2 36273455
2026 SLD5/GINS4 controls dynein-dependent centrosome maturation and exposes a candidate mitotic vulnerability in cancer. bioRxiv : the preprint server for biology 0 42182163
2025 GINS4 Promotes Neonatal Bronchopulmonary Dysplasia via Driving Phosphorylation and Acetylation of p65 NF-κB. Molecular biotechnology 0 41144169
2025 The α5-nAChR/GINS4 axis contributed to nicotine-promoted lung adenocarcinoma progression. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 0 41192616

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