Affinage

GINS4

DNA replication complex GINS protein SLD5 · UniProt Q9BRT9

Length
223 aa
Mass
26.0 kDa
Annotated
2026-04-28
19 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GINS4 (SLD5) is a core subunit of the tetrameric GINS complex essential for DNA replication, centrosome integrity, cell cycle progression, and suppression of ferroptosis. As a GINS subunit, it participates in CMG helicase assembly and activation—recruiting SIK1 kinase to phosphorylate MCM2 for helicase firing (PMID:27592030)—and its disruption causes embryonic lethality, DNA damage accumulation, and impaired GINS complex assembly that selectively blocks NK cell differentiation (PMID:24244394, PMID:25334017, PMID:36345943). Beyond replication, GINS4 localizes to centrosomes where it maintains centriolar satellite clustering and spindle pole integrity during mitosis (PMID:29061732), directly binds and activates Rac1/CDC42 GTPases to promote cell migration (PMID:31754397), and suppresses p53-mediated ferroptosis by activating Snail to antagonize p53 acetylation at K351 (PMID:37018198). Biallelic partial loss-of-function mutations in GINS4 cause a human immunodeficiency characterized by defective NK cell development (PMID:36345943).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 Medium

    Identification of GINS4 as a PSF1-interacting partner established it as a candidate GINS complex subunit involved in proliferating cell populations.

    Evidence Yeast two-hybrid screen and co-localization by immunofluorescence in human cells

    PMID:16338220

    Open questions at the time
    • Interaction mapped only by yeast two-hybrid without endogenous Co-IP
    • Functional consequence of the interaction not tested
    • No evidence yet for role in DNA replication per se
  2. 2010 Medium

    Genetic loss-of-function of the Drosophila GINS4 ortholog demonstrated that it is required for normal S and M phase progression and chromosomal stability, anchoring it functionally within the CMG helicase complex.

    Evidence Co-immunoprecipitation with Psf1/Psf2/Mcm10 and mutant cytological analysis in Drosophila

    PMID:20709026

    Open questions at the time
    • Phenotype described in Drosophila only; mammalian validation pending
    • Direct contribution to helicase enzymatic activity not tested
  3. 2013 High

    Mouse knockout established that GINS4 is indispensable for mammalian cell proliferation and embryonic viability, confirming its non-redundant role in vivo.

    Evidence Targeted gene disruption in mice; peri-implantation lethality with inner cell mass proliferation defect

    PMID:24244394

    Open questions at the time
    • Molecular mechanism of lethality (replication vs. other functions) not dissected
    • Conditional knockout in specific tissues not performed
  4. 2014 Medium

    Knockdown experiments revealed that GINS4 protects normal cells from DNA damage and facilitates DNA repair, extending its function beyond replication fork progression.

    Evidence siRNA knockdown with γH2AX foci, comet assay, and cell cycle analysis in normal vs. cancer cells

    PMID:25334017

    Open questions at the time
    • Mechanism linking GINS4 to DNA repair pathway not identified
    • Differential response between normal and cancer cells unexplained at the molecular level
  5. 2016 High

    Discovery that GINS4 recruits SIK1 kinase to chromatin at S-phase onset to phosphorylate MCM2 provided a direct mechanism for how GINS4 participates in replicative helicase activation.

    Evidence Co-immunoprecipitation, chromatin fractionation, in vitro kinase assay with site-directed mutagenesis, siRNA depletion

    PMID:27592030

    Open questions at the time
    • Whether SIK1 recruitment is the sole mechanism of GINS4-dependent MCM activation is unknown
    • Structural basis of the GINS4–SIK1 interaction not resolved
  6. 2017 High

    Localization of GINS4 to centrosomes and its requirement for centriolar satellite clustering revealed a replication-independent mitotic function in maintaining spindle pole integrity.

    Evidence Immunofluorescence, siRNA knockdown, live imaging, epistasis with CENP-E/Kid/HSET inhibition in human cells

    PMID:29061732

    Open questions at the time
    • How GINS4 is targeted to centrosomes is unknown
    • Whether centrosomal and replication functions are coordinately regulated is untested
  7. 2019 High

    Direct binding and activation of Rac1 and CDC42 GTPases by GINS4 established a non-replicative signaling role in cell migration and metastasis.

    Evidence GST pull-down, GTPase activation assays, cDNA array, in vitro and in vivo gastric cancer functional assays

    PMID:31754397

    Open questions at the time
    • Structural determinants of GINS4–Rac1/CDC42 interaction unknown
    • Whether GTPase activation occurs through GEF-like activity or displacement of GDI not determined
  8. 2019 Medium

    Identification of GINS4 as a common target of viral matrix proteins (influenza M1, and later VSV/SeV/HIV) that exploit it to induce G0/G1 arrest revealed GINS4 as a node in host–virus cell cycle regulation.

    Evidence Yeast two-hybrid, Co-IP, cell cycle rescue by SLD5 overexpression, transgenic mouse infection model; extended to multiple viruses in 2021

    PMID:31050118 PMID:34882534

    Open questions at the time
    • Mechanism by which viral matrix protein binding to GINS4 triggers G0/G1 arrest not defined
    • Whether the interaction surface overlaps with GINS complex assembly is unknown
    • Findings from a single laboratory; independent replication pending
  9. 2022 High

    Human biallelic GINS4 mutations causing impaired GINS complex assembly and selective NK cell developmental failure defined GINS4 as a Mendelian immunodeficiency gene and demonstrated lineage-specific sensitivity to partial GINS loss.

    Evidence Exome sequencing, GINS4 knockdown, GINS complex assembly Co-IP, in vitro NK cell differentiation assay

    PMID:36345943

    Open questions at the time
    • Why NK cells are selectively affected among immune lineages is unclear
    • Whether residual GINS4 function supports replication adequately in other lineages not tested in patients
  10. 2023 High

    GINS4 was shown to suppress p53-mediated ferroptosis via a Snail–p53-K351 acetylation axis, revealing a cell-death regulatory function particularly active in G2/M phase.

    Evidence CRISPR/Cas9 knockout, ferroptosis assays, p53-K351 site-directed mutagenesis, cell cycle fractionation

    PMID:37018198

    Open questions at the time
    • How GINS4 activates Snail transcription or stability is not defined
    • Whether this ferroptosis-suppressive function operates independently of the GINS replication complex is unclear
  11. 2025 Medium

    GINS4 was found to interact with POLE2 and p65 NF-κB, linking it to PI3K/AKT signaling in hepatocellular carcinoma and to NF-κB-driven inflammatory cytokine expression in lung injury, respectively.

    Evidence Co-immunoprecipitation, knockdown/overexpression rescue, xenograft models (POLE2); Co-IP with p65 phosphorylation/acetylation readouts in neonatal rat BPD model (NF-κB)

    PMID:40081544 PMID:41144169

    Open questions at the time
    • POLE2 binding predicted computationally and validated by single-lab Co-IP only
    • Mechanism by which GINS4 promotes p65 post-translational modifications not identified
    • Independence of these signaling roles from GINS complex context not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GINS4's replication-dependent and replication-independent functions (centrosome maintenance, GTPase activation, ferroptosis suppression, NF-κB signaling) are structurally partitioned and coordinately regulated remains an open question.
  • No structural model distinguishing GINS-complex-bound vs. free GINS4 interaction surfaces
  • No temporal or spatial separation of replication vs. non-replication functions resolved in single cells
  • Lineage-specific essentiality mechanisms (e.g., NK cells) lack molecular explanation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-69306 DNA Replication 4 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CDC42MCM2POLE2PSF1RAC1RELASIK1SNAI1
Complex memberships
CMG helicase (CDC45-MCM2-7-GINS)GINS complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 GINS4 (SLD5) was identified as a PSF1-binding protein via yeast two-hybrid; SLD5 interacts with the central region of PSF1 and co-localizes with PSF1 when overexpressed, suggesting cooperation in immature cell proliferation. Yeast two-hybrid, co-localization by immunofluorescence Biochemical and biophysical research communications Medium 16338220
2010 Drosophila Sld5 (GINS4 ortholog) interacts with Psf1, Psf2, and Mcm10; mutations in Sld5 cause M and S phase delays with chromosomal instability, establishing its role in the CMG helicase complex and genomic integrity. Co-immunoprecipitation, genetic loss-of-function in Drosophila with cell cycle and cytological readouts 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 peri-implantation stage, demonstrating SLD5 is essential for early embryogenesis and cell proliferation. Gene knockout in mice with histological and proliferation readouts PloS one High 24244394
2014 Attenuation of SLD5 expression causes marked DNA damage in both normal and cancer cells, and delays DNA repair and cell cycle restoration specifically in normal cells but not in cancer cells, indicating SLD5 has a protective role against DNA damage beyond its DNA replication function. siRNA knockdown with DNA damage assays (γH2AX), cell cycle analysis, comet assay PloS one Medium 25334017
2016 GINS4 (Sld5) recruits SIK1 (salt-inducible kinase 1) to replication sites at the onset of S phase by direct interaction; SIK1 then phosphorylates MCM2 at five conserved N-terminal residues, which is essential for MCM helicase activation. Co-immunoprecipitation, chromatin fractionation, in vitro kinase assay, site-directed mutagenesis, siRNA depletion Cellular signalling High 27592030
2017 Sld5 localizes to centrosomes and is required for maintaining centriolar satellites clustered around centrosomes; depletion of Sld5 disperses satellites, prevents pericentrin recruitment, and renders centrosomes unable to resist CENP-E- and Kid-mediated microtubular pulling forces, causing monocentriolar and acentriolar spindle poles during chromosome congression. Immunofluorescence localization, siRNA knockdown, live imaging, epistasis with CENP-E/Kid/HSET inhibition Molecular and cellular biology High 29061732
2019 GINS4 directly binds Rac1 and CDC42 (demonstrated by co-IP and GST pull-down), activating their GTPase activity and downstream pathways, thereby promoting gastric cancer cell growth and metastasis. Co-immunoprecipitation, GST pull-down, GTPase activation assays, cDNA array, in vitro and in vivo functional assays Theranostics High 31754397
2019 LSH (lymphoid-specific helicase) binds to the 3'UTR of GINS4 mRNA and stabilizes it, increasing GINS4 expression at the post-transcriptional level in non-small cell lung cancer. RNA immunoprecipitation, Co-immunoprecipitation, overexpression/knockdown rescue experiments Journal of experimental & clinical cancer research Medium 31253190
2019 Influenza virus M1 protein interacts with SLD5 and blocks host cell cycle at G0/G1; overexpression of SLD5 partially rescues M1-induced G0/G1 arrest, demonstrating SLD5 is a target of viral cell cycle manipulation. Yeast two-hybrid, co-immunoprecipitation, cell cycle analysis by flow cytometry, SLD5 transgenic mouse infection model Cellular microbiology Medium 31050118
2021 Matrix proteins of VSV, SeV, and HIV also interact with SLD5 and induce G0/G1 cell cycle arrest; SLD5 overexpression partially rescues VSV/SeV-induced arrest and suppresses VSV replication while enhancing type I interferon signaling, indicating targeting SLD5 is a common viral strategy. Co-immunoprecipitation, cell cycle analysis, viral replication assays, interferon signaling measurement The Journal of general virology Medium 34882534
2022 Partial loss-of-function biallelic mutations in GINS4 impair GINS complex assembly and expression, causing delayed cell cycle progression and a cell-intrinsic defect in NK cell development without increased replication stress, defining GINS4 as necessary for NK cell differentiation. Exome sequencing, GINS4 knockdown, GINS complex assembly assay (Co-IP/western blot), in vitro NK cell differentiation, cell cycle analysis JCI insight High 36345943
2023 GINS4 suppresses p53 stability by activating Snail, which antagonizes p53 acetylation; p53 lysine residue K351 is the key acetylation site through which GINS4 inhibits p53-mediated ferroptosis, particularly in G2/M cells. CRISPR/Cas9 KO, ferroptosis assays, western blot for p53 acetylation, site-directed mutagenesis of p53 K351, cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America High 37018198
2025 GINS4 directly binds POLE2 (DNA polymerase epsilon subunit 2); GINS4 silencing reduces POLE2 expression and suppresses PI3K/AKT signaling, while POLE2 overexpression reverses the effects of GINS4 knockdown on proliferation, cell cycle, and ferroptosis in hepatocellular carcinoma cells. STRING/HDOCK binding prediction, Co-immunoprecipitation/co-localization, GINS4 knockdown, POLE2 overexpression rescue, in vivo xenograft Cellular signalling Medium 40081544
2025 GINS4 directly interacts with p65 NF-κB and promotes its phosphorylation and acetylation, driving inflammatory cytokine expression (IL-6, IL-1β, IL-18, IFN-γ, TNF-α) in hyperoxia-induced lung injury. Co-immunoprecipitation, western blot for p65 phosphorylation/acetylation, in vivo neonatal rat BPD model Molecular biotechnology Medium 41144169
2025 α5-nAChR (encoded by CHRNA5) mediates nicotine-induced GINS4 expression via STAT3 signaling, promoting LUAD cell proliferation, migration, and invasion; CHRNA5 silencing reduces GINS4 expression. siRNA knockdown, western blot, in vitro functional assays, xenograft models Food and chemical toxicology Medium 41192616

Source papers

Stage 0 corpus · 19 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 46 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
2010 Drosophila Sld5 is essential for normal cell cycle progression and maintenance of genomic integrity. Biochemical and biophysical research communications 19 20709026
2022 Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia. JCI insight 18 36345943
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
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