Affinage

CIZ1

Cip1-interacting zinc finger protein · UniProt Q9ULV3

Length
898 aa
Mass
100.0 kDa
Annotated
2026-06-09
46 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIZ1 is a nuclear matrix-associated protein that couples cell-cycle-regulated DNA replication initiation to the spatial organization and epigenetic maintenance of chromatin (PMID:15585571, PMID:17182902). Through an N-terminal replication domain it cooperates with cyclin E and then cyclin A–CDK2 — which it engages sequentially via distinct cyclin-binding motifs, cyclin A displacing cyclin E — to promote initiation of mammalian DNA replication at licensed origins, immobilizing cyclin-A kinase at subnuclear sites; depletion blocks S-phase entry despite chromatin loading of MCM and PCNA (PMID:15585571, PMID:20215406). Cyclin-A–CDK2 then provides negative feedback by phosphorylating CIZ1 at threonines 144/192/293, which disrupts the CIZ1–cyclin-A–CDK2 interaction and blocks further initiation while preserving nuclear-matrix and CDC6 binding (PMID:25736292). A C-terminal matrin-3 anchor domain mediates CIZ1 dimerization and immobilizes the protein at replication factories, and the same anchor tethers CIZ1 to the inactive X chromosome through direct, Repeat-E–dependent binding to Xist RNA, where it is required for focal Xist localization, transient S-phase repositioning of Xi, and Polycomb-mediated deposition of H2AK119ub1 and H3K27me3 (PMID:17182902, PMID:28546514, PMID:28923964, PMID:30692537, PMID:41626693). Glutamine-rich prion-like domains drive CIZ1 self-assembly into fibrillar networks that build these supramolecular Xi assemblies, and Aurora kinase B phosphorylates the disordered C-terminal extensions in mitosis to release CIZ1 from RNA and dissolve the assemblies (PMID:35289833, PMID:41626693). CIZ1 additionally controls the H4K20me1-dependent nuclear condensation that accompanies quiescence entry, and loss of CIZ1 causes replication stress, restriction-point bypass, and tumor-suppressor failure: CIZ1-null mice develop leukemias and a female-specific lymphoproliferative disorder (PMID:23583447, PMID:28546514, PMID:37580709). A CIZ1 missense mutation that alters its splicing and nuclear localization is causal for adult-onset primary cervical dystonia (PMID:22447717). Beyond its replication and chromatin roles, CIZ1 binds p21(Cip1/Waf1) and regulates its localization, and engages ERH, DHX9, TCF4, and YAP to modulate cell-cycle progression and transcriptional signaling (PMID:10529385, PMID:18081865, PMID:33093612, PMID:36047590).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 Medium

    Established the first molecular handle on CIZ1 by showing it binds the CDK2-interacting region of the CDK inhibitor p21 and controls p21 subcellular localization, placing CIZ1 at the cell-cycle machinery.

    Evidence Yeast two-hybrid, co-IP and immunofluorescence in U2-OS cells

    PMID:10529385

    Open questions at the time
    • Functional consequence for cell-cycle progression not tested
    • Did not address whether p21 binding competes with other CIZ1 partners
  2. 2003 Medium

    Asked whether CIZ1 contacts DNA directly and defined a consensus binding sequence, indicating a chromatin-associated rather than purely protein-scaffolding role.

    Evidence SAAB sequence selection and EMSA, with nuclear immunofluorescence across tissues

    PMID:12824700

    Open questions at the time
    • Genomic targets of the consensus in vivo not identified
    • Link between DNA binding and replication function not established
  3. 2004 High

    Defined CIZ1's core function as a positive regulator of mammalian DNA replication initiation acting downstream of origin licensing, the keystone mechanistic finding.

    Evidence Cell-free replication reconstitution with recombinant protein, GFP overexpression, CDK-site mutagenesis, RNAi with BrdU and chromatin-bound MCM3/PCNA analysis

    PMID:15585571

    Open questions at the time
    • Identity of the cyclin/CDK partner driving initiation not yet defined
    • Did not resolve how CIZ1 is positioned at origins
  4. 2007 High

    Resolved how CIZ1 is spatially organized, mapping a C-terminal nuclear-matrix anchor (aa 708–830) that immobilizes CIZ1 at replication factories in a cell-cycle-dependent manner, while N-terminal domains specify focal patterning.

    Evidence GFP-fragment domain mapping, nuclear matrix fractionation, co-localization with BrdU replication sites

    PMID:17182902

    Open questions at the time
    • Molecular nature of the matrix attachment partner not defined
    • How anchoring is timed to late G1/early S not resolved
  5. 2007 Medium

    Showed that splice variants and partner recruitment shape CIZ1 function: a cancer-associated ΔE4 isoform separates replication activity from foci formation and acts dominant-negatively, and CIZ1 recruits ERH to replication foci through a region overlapping the p21 site.

    Evidence Exon-trap splicing assay and dominant-negative coexpression (ΔE4); yeast two-hybrid, GST pull-down and MS (ERH)

    PMID:17508423 PMID:18081865

    Open questions at the time
    • Functional role of ERH recruitment at replication foci untested
    • Whether p21 and ERH binding are mutually exclusive in vivo not shown
  6. 2008 Medium

    Refined the matrix-association determinant to a 28-residue glutamine-rich element encoded by exon 8, linking alternative splicing of this region to CIZ1 foci formation.

    Evidence Immunofluorescence, nuclear matrix fractionation and deletion analysis in transfected cells

    PMID:18583151

    Open questions at the time
    • Did not connect the Q-rich element to later-defined prion-like self-assembly
    • Physiological regulation of exon 8 splicing not addressed
  7. 2010 High

    Identified the cyclin partners and the mechanism of initiation, showing CIZ1 binds cyclin E then cyclin A through distinct motifs and immobilizes cyclin-A–CDK2 at subnuclear sites to drive replication.

    Evidence Cell-free reconstitution with recombinant cyclin-A–CDK2 and CIZ1, co-IP cyclin displacement, RNAi with cyclin A localization imaging

    PMID:20215406

    Open questions at the time
    • How the sequential cyclin switch is temporally controlled not resolved
    • Origin specificity of CIZ1-targeted cyclin A not mapped
  8. 2012 Medium

    Extended CIZ1 function beyond somatic replication, linking it to germ-cell cyclin A1 and DSB repair, and identifying a causal dystonia mutation that alters CIZ1 splicing and localization.

    Evidence Co-IP and in vitro plasmid repair assay in testis extract; exome sequencing and minigene splicing assay (S264G)

    PMID:22366453 PMID:22447717

    Open questions at the time
    • Direct repair substrate and mechanism for CIZ1 in germ cells not defined
    • How the dystonia mutation produces neuronal pathology not established
  9. 2013 Medium

    Established CIZ1 as a bona fide tumor suppressor in vivo, with null cells sensitive to replication stress and prone to transformation and null mice developing leukemias.

    Evidence CIZ1-knockout mice, hydroxyurea sensitivity, oncogene transformation in MEFs, retroviral insertional mutagenesis

    PMID:23583447

    Open questions at the time
    • Mechanistic link between replication-stress sensitivity and tumorigenesis not fully resolved
    • Tissue specificity of tumor spectrum unexplained
  10. 2015 High

    Defined a negative feedback loop in which cyclin-A–CDK2 phosphorylates CIZ1 at T144/T192/T293 to terminate further initiation while sparing matrix and CDC6 binding.

    Evidence Phosphomimetic mutagenesis, cell-free and cell-based replication assays, co-IP, phospho-T192 antibody, immunofluorescence

    PMID:25736292

    Open questions at the time
    • Phosphatase that resets CIZ1 not identified
    • How feedback restricts initiation to once-per-cycle not fully mechanistic
  11. 2017 High

    Revealed a distinct CIZ1 role at the inactive X chromosome, showing its C-terminal anchor binds Repeat E of Xist RNA to retain Xist focally and maintain H3K27me3, establishing CIZ1 as an Xist-tethering factor.

    Evidence CIZ1-null mice with rescue, RNA FISH, STORM single-molecule imaging, reciprocal CIZ1/Repeat-E deletions, H3K27me3 ChIP

    PMID:28546514 PMID:28923964

    Open questions at the time
    • How RNA binding and matrix anchoring are coordinated not resolved
    • Whether the same anchor mediates both replication and Xi roles unresolved at this stage
  12. 2019 High

    Connected CIZ1's replication and Xi functions by showing CIZ1 is required for S-phase repositioning of Xi and for stable PRC1/PRC2 deposition (H2AK119ub1, H3K27me3) and EZH2 retention.

    Evidence Live imaging and immunofluorescence of Xi position, CIZ1-null MEFs, histone-mark ChIP, EZH2 fractionation, transcriptomics

    PMID:30692537

    Open questions at the time
    • Direct link between Xi repositioning and PRC retention mechanistically unproven
    • How replication timing intersects with CIZ1-Xi assembly unresolved
  13. 2020 Medium

    Added a nucleolar dimension, identifying DHX9 as a CIZ1 partner whose RNA Pol I–dependent co-localization supports G1-to-S progression.

    Evidence Molecular panning/MS, in vitro binding, co-localization with Pol I inhibition, siRNA with cell-cycle analysis

    PMID:33093612

    Open questions at the time
    • Mechanism by which CIZ1–DHX9 promotes S-phase entry not defined
    • Single-lab in vitro interaction without reciprocal in vivo validation
  14. 2022 High

    Provided the structural and biophysical basis for CIZ1 assembly, defining two independent Xist-binding domains, two glutamine-rich prion-like domains driving fibrillar self-assembly, and the atomic ERH–CIZ1 heterotetramer interface.

    Evidence RNA-IP domain mapping, in vitro self-assembly assays and rescue in null cells (PLDs); crystal structure with interface mutagenesis (ERH)

    PMID:35289833 PMID:36047590

    Open questions at the time
    • Functional role of ERH binding in replication or Xi assembly not established
    • How PLD-driven self-assembly is regulated in cells not resolved
  15. 2023 Medium

    Linked CIZ1 to quiescence by showing it sustains H4K20me1 needed for nuclear condensation, and that repeated quiescence cycling without CIZ1 drives genome instability and transformation.

    Evidence CIZ1-null fibroblasts, H4K20me1 ChIP/IF, nuclear morphology imaging, SET8 manipulation, rescue and quiescence cycling/transformation assays

    PMID:37580709

    Open questions at the time
    • How CIZ1 supports SET8-dependent H4K20me1 mechanistically unknown
    • Causal chain from condensation defect to transformation not fully established
  16. 2025 High

    Defined the mitotic regulation and structural architecture of the CIZ1 anchor, showing the matrin-3 domain dimerizes into a folded core with disordered extensions that AURKB phosphorylates to release CIZ1 from RNA and Xi during prometaphase, and that the anchor domain acts dominant-negatively to disrupt post-mitotic Xi reassembly and Polycomb marks.

    Evidence MS interactome, structure-informed phosphomimetic/deletion mutagenesis, RNA-IP, AURKB inhibition, prometaphase imaging; ectopic anchor-domain dominant-negative model with histone-mark/Xist FISH and tumor transcriptomics

    PMID:40067149 PMID:41626693

    Open questions at the time
    • How AURKB phosphorylation is reversed to permit reassembly not resolved
    • Whether mitotic release is selectively used at Xi versus replication factories unclear
  17. 2025 Medium

    Placed CIZ1 within an upstream regulatory pathway by showing the Mediator kinase module (Med12/CDK8) is required for Xist-directed CIZ1 recruitment and H3K27me3 accumulation at the onset of X inactivation.

    Evidence Med12 mutation and CDK8 perturbation in an ESC X-inactivation model with CIZ1 recruitment imaging and H3K27me3 ChIP

    PMID:41200585

    Open questions at the time
    • Whether Mediator kinase acts directly on CIZ1 or via intermediates unknown
    • Single-lab genetic epistasis without biochemical mechanism

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CIZ1's replication-initiation activity and Xist-tethering activity are mechanistically integrated through a shared anchor and self-assembly machinery, and what resets the system between cell cycles, remains open.
  • No phosphatase or reset mechanism for cyclin-A or AURKB phosphorylation identified
  • Direct structural model of CIZ1 at an origin versus at Xi not resolved
  • Mechanism linking transcriptional coactivator roles (YAP/TCF4/ERα) to the matrix/replication functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0140110 transcription regulator activity 3 GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2 GO:0005730 nucleolus 1
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-1640170 Cell Cycle 3 R-HSA-69306 DNA Replication 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 2
Partners
CCNA2CCNE1CDC6CDK2CDKN1ADHX9ERHYAP1
Complex memberships
CIZ1–Xist RNA assembly at inactive X chromosomeERH–CIZ1 2:2 heterotetramer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 CIZ1 (Ciz1) binds directly to the N-terminal, CDK2-interacting part of p21(Cip1/Waf1) through a region of ~150 amino acids containing its first zinc-finger motif; this interaction is disrupted by overexpression of CDK2. Coexpression of Ciz1 with p21 induces cytoplasmic redistribution of p21, showing Ciz1 regulates p21 subcellular localization. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, overexpression in U2-OS cells Biochemical and biophysical research communications Medium 10529385
2003 CIZ1 binds DNA directly and recognizes the consensus sequence ARYSR(0-2)YYAC, as determined by a modified SAAB (selected and amplified binding) method and confirmed by electrophoretic mobility shift assays. CIZ1 localizes to the nucleus in a broad range of tissues. SAAB sequence selection, EMSA, immunofluorescence, Northern blot Journal of biomedical science Medium 12824700
2004 Ciz1 promotes initiation of mammalian DNA replication: recombinant Ciz1 increases the number of nuclei initiating DNA replication in a cell-free reconstitution system; GFP-Ciz1 stimulates DNA synthesis in intact cells; mutation of putative CDK phosphorylation sites at threonines 191/192 alters Ciz1 activity in vitro. Endogenous Ciz1 localizes to nuclear foci co-localizing with PCNA during S phase, and RNAi depletion of Ciz1 inhibits S-phase entry with accumulation of chromatin-bound Mcm3 and PCNA but failure to synthesize DNA. Cell-free DNA replication reconstitution assay, GFP overexpression in intact cells, site-directed mutagenesis, immunofluorescence co-localization with PCNA, RNAi knockdown with flow cytometry and BrdU incorporation Journal of cell science High 15585571
2006 Ciz1 functions as a coactivator of estrogen receptor alpha (ERα): Ciz1 protein binds directly to ERα-associated chromatin, enhances ER transactivation activity, and promotes recruitment of the ER complex to target gene chromatin. Ciz1 overexpression confers estrogen hypersensitivity and promotes anchorage-independent growth and tumorigenicity in breast cancer cells. Chromatin immunoprecipitation (ChIP), reporter transactivation assay, proliferation and colony formation assays, xenograft Cancer research Medium 17108141
2007 CIZ1 is immobilized at the nuclear matrix through sequences in its C-terminal third (amino acids 708–830), in a cell-cycle-dependent manner coinciding with late G1/early S phase. Matrix-associated CIZ1 foci co-localize with sites of newly synthesized DNA (replication factories). N-terminal domains are additionally required to specify focal organization, while C-terminal domains alone are sufficient for nuclear matrix immobilization. GFP-tagged fragment analysis, nuclease and high-salt extraction (nuclear matrix fractionation), immunofluorescence co-localization with BrdU-labeled replication sites Journal of cell science High 17182902
2007 Ciz1 interacts with ERH (enhancer of rudimentary homolog) through residues 531–644 encompassing its first zinc finger motif; this region overlaps the p21(Cip1/Waf1)-binding site, suggesting competitive binding. When coexpressed, Ciz1 recruits ERH to DNA replication foci in HeLa cells. Yeast two-hybrid, GST pull-down assay, tandem MS, immunofluorescence co-localization The FEBS journal Medium 18081865
2007 A cancer-associated alternatively spliced CIZ1 variant lacking exon 4 (ΔE4) retains replication activity but fails to form subnuclear foci. Coexpression of mouse ΔE4 with wild-type Ciz1 prevents normal Ciz1 focal localization, exerting a dominant-negative effect on foci formation. Exon 4 skipping is caused by expansion of an intronic mononucleotide repeat in Ewing tumor cell lines. Exon-trap splicing assay, immunofluorescence, dominant-negative coexpression experiment, sequencing Human mutation Medium 17508423
2008 A CIZ1 isoform lacking the glutamine-rich region encoded by exon 8 (due to alternative splicing) loses the ability to associate with the nuclear matrix and form nuclear foci; a minimal 28 amino acid sequence within this glutamine-rich region is required for nuclear matrix association and foci formation. Immunofluorescence, nuclear matrix fractionation, domain deletion analysis in transfected cells Molecular and cellular neurosciences Medium 18583151
2010 Ciz1 interacts with cyclin E and cyclin A sequentially through distinct cyclin-binding motifs; cyclin A displaces cyclin E from Ciz1. In cell-free assays, recombinant cyclin-A-CDK2 and recombinant Ciz1 cooperate to promote initiation of DNA replication in late G1-phase nuclei. Ciz1 immobilizes cyclin A in isolated nuclei and RNAi depletion of Ciz1 impairs cyclin A nuclear immobilization, indicating Ciz1 targets cyclin-A kinase to specific subnuclear sites. Cell-free DNA replication reconstitution assay with recombinant proteins, co-immunoprecipitation (cyclin E/A displacement), RNAi knockdown with immunofluorescence for cyclin A localization Journal of cell science High 20215406
2012 A missense mutation in CIZ1 (c.790A>G, p.S264G), identified as causal for adult-onset primary cervical dystonia, alters CIZ1 splicing patterns (demonstrated by minigene assay) and alters the nuclear localization of CIZ1. Exome sequencing, minigene splicing assay, immunofluorescence for nuclear localization Annals of neurology Medium 22447717
2012 In non-proliferating spermatocytes, CIZ1 interacts with germ-cell-specific cyclin A1 (distinct from somatic cyclin A2). Antibody depletion of CIZ1 from testis extract reduces the capacity to repair digested plasmid DNA in vitro, suggesting a post-replicative role for CIZ1 in DNA double-strand break repair in germ cells. Co-immunoprecipitation (CIZ1–cyclin A1), in vitro plasmid repair assay with antibody depletion Journal of cell science Medium 22366453
2013 CIZ1-null MEFs are sensitive to hydroxyurea-induced replication stress and susceptible to oncogene-induced cellular transformation; Ciz1-null mice developed various leukemias in a retroviral insertional mutagenesis model, establishing CIZ1 as a tumor suppressor in vivo. Knockout mouse model, hydroxyurea sensitivity assay, oncogene transformation assay in MEFs, retroviral insertional mutagenesis FEBS letters Medium 23583447
2015 Cyclin-A-CDK2 negatively regulates CIZ1 by phosphorylating it at threonines 144, 192, and 293. Phosphomimetic CIZ1 mutants fail to promote DNA replication in cell-free and cell-based assays and exert a dominant-negative effect on PCNA recruitment to replisomes. Phosphorylation blocks CIZ1 interaction with cyclin-A-CDK2 and prevents recruitment of endogenous cyclin A to the nuclear matrix; however, phosphomimetic CIZ1 retains nuclear matrix binding and interaction with CDC6. Phospho-T192-specific antibodies confirm that phosphorylation occurs during S phase and G2 at post-initiation cyclin-A-CDK2 concentrations. Site-directed mutagenesis (phosphomimetic), cell-free DNA replication assay, cell-based replication assay, co-immunoprecipitation, phospho-specific antibody, immunofluorescence Journal of cell science High 25736292
2014 CIZ1 interacts with TCF4 and activates β-catenin/TCF signaling in gallbladder cancer cells; CIZ1 overexpression promotes growth and migration while knockdown inhibits growth, migration, and tumorigenesis in vitro and in vivo. Co-immunoprecipitation (CIZ1–TCF4), luciferase reporter assay for β-catenin/TCF, siRNA knockdown, xenograft Tumour biology Medium 25427641
2016 CIZ1 activates YAP transcriptional activity in hepatocellular carcinoma cells by physically interacting with YAP; the nuclear matrix anchor domain of CIZ1 mediates this interaction. CIZ1 also enhances the YAP–TEAD interaction. Knockdown of CIZ1 impairs YAP transcriptional activity and YAP-dependent cell growth and migration. Co-immunoprecipitation (CIZ1–YAP), domain deletion mapping, luciferase reporter assay (TEAD-dependent), siRNA knockdown Tumour biology Medium 26906552
2017 CIZ1 is recruited to the inactive X chromosome (Xi) in response to Xist RNA expression during the earliest stages of X inactivation in embryonic stem cells. Recruitment requires the C-terminal nuclear matrix anchor domain of CIZ1 and the E repeats of Xist RNA. In CIZ1-null mouse embryonic fibroblasts, Xist RNA localizes diffusely throughout the nucleoplasm rather than focally; re-expression of CIZ1 restores focal Xist localization. CIZ1-null mice display fully penetrant female-specific lymphoproliferative disorder. Immunofluorescence, RNA FISH, CIZ1-null mouse model, re-expression rescue experiment, domain deletion analysis (C-terminal anchor and Xist repeat E) Genes & development High 28546514
2017 CIZ1 interacts directly with Xist RNA specifically through the highly repetitive Repeat E motif within Xist exon 7, shown at single-molecule level by STORM microscopy. Genetic loss of CIZ1 or deletion of Repeat E phenocopy each other, causing Xist RNA to delocalize from Xi into the nucleoplasm. Overexpression of CIZ1 similarly delocalizes Xist. CIZ1 delocalization is accompanied by decreased H3K27me3 at Xi. STORM super-resolution microscopy, genetic deletion (CIZ1 KO and Repeat E deletion), RNA FISH, ChIP (H3K27me3) Proceedings of the National Academy of Sciences of the United States of America High 28923964
2019 CIZ1 is required for transient relocation of Xi from the nuclear periphery toward the nuclear interior during its replication in S phase. In CIZ1-null primary MEFs, this relocation is compromised and is accompanied by loss of PRC-mediated H2AK119Ub1 and H3K27me3, increased solubility of PRC2 catalytic subunit EZH2, and genome-wide deregulation of polycomb-regulated genes. Live-cell imaging and immunofluorescence (Xi position in S phase), CIZ1-null MEFs, ChIP (H2AK119Ub1, H3K27me3), nuclear fractionation (EZH2 solubility), transcriptomics Nature communications High 30692537
2020 CIZ1 interacts with DHX9 in vitro, and the two proteins dynamically co-localize within the nucleolus from early to mid S phase in an RNA polymerase I activity-dependent manner. Depletion of DHX9 abolishes CIZ1–DHX9 nucleolar co-localization and reduces G1-to-S-phase cell cycle progression in mouse fibroblasts. Molecular panning, mass spectrometry, in vitro binding, immunofluorescence co-localization, RNA Pol I inhibition, siRNA knockdown with cell cycle analysis Scientific reports Medium 33093612
2022 CIZ1 undergoes two direct and independent interactions with Xist RNA, mediated by separate N-terminal and C-terminal domains. Two alternatively spliced glutamine-rich prion-like domains (PLD1 and PLD2) modulate CIZ1 assembly at Xi: PLD1 is required for both de novo assembly and accumulation at preexisting CIZ1-Xi assemblies and drives formation of a stable fibrillar network in vitro; PLD2 is required only for de novo assembly in CIZ1-null cells. CIZ1 self-assemblies formed in vitro are modulated by these PLDs. RNA immunoprecipitation (N- and C-terminal domain mapping), immunofluorescence in wild-type and CIZ1-null cells, in vitro self-assembly assay, domain deletion/mutation analysis The Journal of cell biology High 35289833
2022 The crystal structure of ERH bound to CIZ1 reveals that the ERH dimer binds two CIZ1 fragments (upstream of CIZ1's first zinc finger) to form a 2:2 heterotetramer. CIZ1 forms intermolecular antiparallel β-strands with ERH, and the ERH–CIZ1 binding surface is distinct from known ERH-binding ligands. Interface mutagenesis validated the interaction. Crystal structure determination, GST pull-down assay, site-directed mutagenesis of binding interface The FEBS journal High 36047590
2023 CIZ1-null primary murine fibroblasts have reduced H4K20me1 (a mark placed by SET8), which compromises nuclear condensation on entry to quiescence. Re-expression of CIZ1 in null cells partially reverts the condensation defect. Repeated quiescence entry/exit cycles in CIZ1-null cells generate expanded, mechanically stressed nuclei, DNA damage checkpoint activation, and emergence of transformed colonies. CIZ1-null mouse fibroblasts, ChIP/immunofluorescence (H4K20me1), nuclear morphology imaging, SET8 manipulation, CIZ1 re-expression rescue, quiescence cycling assay, transformation assay BMC biology Medium 37580709
2025 CIZ1 is released from Xi during prometaphase under regulation of Aurora Kinase B (AURKB). The C-terminal 179/181 amino acids of human/mouse CIZ1 encode a matrin-3 domain that mediates CIZ1 dimerization forming a compact folded core with disordered C-terminal extensions. AURKB phosphorylates three conserved sites in these C-terminal extensions; phosphomimetic mutation at these sites releases CIZ1 from nuclear anchor points and abolishes CIZ1 interaction with RNA (including Xist) without affecting interaction with chromatin or nuclear matrix proteins. Mass spectrometry (56 interacting partners of C-terminal fragment), phosphomimetic and deletion mutagenesis, immunofluorescence (prometaphase CIZ1 release), RNA immunoprecipitation, AURKB inhibitor treatment Nucleic acids research High 41626693
2025 CIZ1 C-terminal anchor domain (AD) exerts a dominant-negative effect on CIZ1-Xi assembly reformation after mitosis, leading to abnormal assemblies depleted of H2AK119ub1 and H3K27me3 and loss of Xist focal localization, with consequent genome-wide deregulation of gene expression in a pattern consistent with unscheduled chromatin exposure to modifying enzymes. Ectopic AD expression (dominant-negative model), immunofluorescence (H2AK119ub1, H3K27me3, Xist RNA FISH), transcriptomics, human tumor transcriptome analysis The Journal of cell biology Medium 40067149
2025 Med12 (a component of the Mediator kinase module with CDK8) is required for CIZ1 recruitment by Xist and H3K27me3 accumulation during initiation of X chromosome inactivation in mouse embryonic stem cells; CDK8 similarly modulates CIZ1 recruitment, placing the Mediator kinase module upstream of CIZ1 in the Xist silencing pathway. Med12 mutation in ESC model of X inactivation, immunofluorescence/RNA FISH for CIZ1 recruitment, CDK8 perturbation, H3K27me3 ChIP Epigenetics reports Medium 41200585
2024 CIZ1 ablation in fibroblasts causes a post-quiescent reduction in G1 length associated with elevated cyclin E1/E2 and A2 expression and enhanced Rb phosphorylation leading to early restriction-point bypass. CIZ1-null cells show deficient cyclin A chromatin binding and require a 2-fold higher CDK activity threshold for initiation of DNA replication, resulting in DNA replication stress in vitro and in vivo. Addition of recombinant CIZ1 reinstates cyclin A chromatin recruitment and restores the normal CDK threshold for initiation of DNA replication, reversing replication stress and increasing replication fork rates. Fucci(CA) live-cell imaging, cell-free DNA replication assay, DNA fiber combing, cyclin E1/E2/A2 expression analysis, Rb phosphorylation assay, recombinant CIZ1 add-back, CIZ1-KO fibroblasts bioRxivpreprint Medium bio_10.1101_2024.09.02.610838

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Mutations in CIZ1 cause adult onset primary cervical dystonia. Annals of neurology 110 22447717
2017 The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory. Genes & development 102 28546514
2017 Repeat E anchors Xist RNA to the inactive X chromosomal compartment through CDKN1A-interacting protein (CIZ1). Proceedings of the National Academy of Sciences of the United States of America 98 28923964
2004 Ciz1 promotes mammalian DNA replication. Journal of cell science 61 15585571
2009 Glucocorticoid receptor activation of the Ciz1-Lcn2 locus by long range interactions. The Journal of biological chemistry 59 19124469
1999 Cloning and characterization of a novel p21(Cip1/Waf1)-interacting zinc finger protein, ciz1. Biochemical and biophysical research communications 57 10529385
2006 Ciz1, a Novel DNA-binding coactivator of the estrogen receptor alpha, confers hypersensitivity to estrogen action. Cancer research 48 17108141
2012 Variant Ciz1 is a circulating biomarker for early-stage lung cancer. Proceedings of the National Academy of Sciences of the United States of America 47 23074256
2007 C-terminal domains deliver the DNA replication factor Ciz1 to the nuclear matrix. Journal of cell science 42 17182902
2020 Dihydroartemisinin inhibits the tumorigenesis and metastasis of breast cancer via downregulating CIZ1 expression associated with TGF-β1 signaling. Life sciences 37 32088211
2010 Ciz1 cooperates with cyclin-A-CDK2 to activate mammalian DNA replication in vitro. Journal of cell science 37 20215406
2003 Ciz1, Cip1 interacting zinc finger protein 1 binds the consensus DNA sequence ARYSR(0-2)YYAC. Journal of biomedical science 36 12824700
2008 Altered splicing in exon 8 of the DNA replication factor CIZ1 affects subnuclear distribution and is associated with Alzheimer's disease. Molecular and cellular neurosciences 30 18583151
2007 Ciz1, a p21 cip1/Waf1-interacting zinc finger protein and DNA replication factor, is a novel molecular partner for human enhancer of rudimentary homolog. The FEBS journal 28 18081865
2018 DNA damage and neurodegenerative phenotypes in aged Ciz1 null mice. Neurobiology of aging 27 29154038
2007 Cancer-associated missplicing of exon 4 influences the subnuclear distribution of the DNA replication factor CIZ1. Human mutation 27 17508423
2015 Cyclin-A-CDK2-mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication. Journal of cell science 26 25736292
2020 Upregulation of lncRNA DANCR functions as an oncogenic role in non-small lung cancer by regulating miR-214-5p/CIZ1 axis. European review for medical and pharmacological sciences 23 32196604
2012 Cancer-associated variant expression and interaction of CIZ1 with cyclin A1 in differentiating male germ cells. Journal of cell science 21 22366453
2010 Differential detection of alternatively spliced variants of Ciz1 in normal and cancer cells using a custom exon-junction microarray. BMC cancer 20 20831784
2014 Ciz1 is a novel predictor of survival in human colon cancer. Experimental biology and medicine (Maywood, N.J.) 19 24928862
2014 CIZ1 promoted the growth and migration of gallbladder cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 19 25427641
2015 Ciz1 promotes tumorigenicity of prostate carcinoma cells. Frontiers in bioscience (Landmark edition) 17 25553473
2013 CIZ1, a p21Cip1/Waf1-interacting protein, functions as a tumor suppressor in vivo. FEBS letters 17 23583447
2013 CIZ1 regulates the proliferation, cycle distribution and colony formation of RKO human colorectal cancer cells. Molecular medicine reports 17 24126760
2016 The Role of Cdkn1A-Interacting Zinc Finger Protein 1 (CIZ1) in DNA Replication and Pathophysiology. International journal of molecular sciences 14 26861296
2022 Prion-like domains drive CIZ1 assembly formation at the inactive X chromosome. The Journal of cell biology 13 35289833
2016 Emerging Roles for Ciz1 in Cell Cycle Regulation and as a Driver of Tumorigenesis. Biomolecules 13 28036012
2015 CIZ1 is upregulated in hepatocellular carcinoma and promotes the growth and migration of the cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 26515335
2016 Motor phenotypes and molecular networks associated with germline deficiency of Ciz1. Experimental neurology 12 27163549
2019 Maintenance of epigenetic landscape requires CIZ1 and is corrupted in differentiated fibroblasts in long-term culture. Nature communications 10 30692537
2019 CIZ1 knockdown suppresses the proliferation of bladder cancer cells by inducing apoptosis. Gene 9 31252164
2016 CIZ1 interacts with YAP and activates its transcriptional activity in hepatocellular carcinoma cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 9 26906552
2020 Identification of DHX9 as a cell cycle regulated nucleolar recruitment factor for CIZ1. Scientific reports 8 33093612
2022 Molecular basis for the recognition of CIZ1 by ERH. The FEBS journal 5 36047590
2018 CIZ1-F, an alternatively spliced variant of the DNA replication protein CIZ1 with distinct expression and localisation, is overrepresented in early stage common solid tumours. Cell cycle (Georgetown, Tex.) 5 30280956
2017 Cardiomyocyte--specific expression of the nuclear matrix protein, CIZ1, stimulates production of mono-nucleated cells with an extended window of proliferation in the postnatal mouse heart. Biology open 3 27934662
2011 Clobetasol synergistically diminishes Ciz1 expression with genistein in U937 cells. Molecular medicine reports 3 22075938
2025 Epigenetic deprogramming by disruption of CIZ1-RNA nuclear assemblies in early-stage breast cancers. The Journal of cell biology 2 40067149
2018 CIZ1 Expression Is Upregulated in Hemangioma of the Tongue. Pathology oncology research : POR 2 30456533
2023 CIZ1 in Xist seeded assemblies at the inactive X chromosome. Frontiers in cell and developmental biology 1 38155839
2018 Consequences of Cre-mediated deletion of Ciz1 exon 5 in mice. FEBS letters 1 30098009
2026 AURKB-driven dissolution of CIZ1-RNA assemblies from the inactive X chromosome in mitosis. Nucleic acids research 0 41626693
2025 Implication of the Mediator kinase module in CIZ1 recruitment and gene silencing by Xist during the initiation of X inactivation. Epigenetics reports 0 41200585
2023 Epigenetic instability caused by absence of CIZ1 drives transformation during quiescence cycles. BMC biology 0 37580709
2023 CIZ1 aggravates gastric cancer progression via mediating FBXL19-AS1 and miR-339-3p. Heliyon 0 37954363

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