Affinage

ORC1

Mitochondrial ornithine transporter 1 · UniProt Q9Y619

Length
301 aa
Mass
32.7 kDa
Annotated
2026-06-10
96 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ORC1 is the largest subunit of the Origin Recognition Complex and the rate-limiting, cell-cycle-regulated factor that licenses metazoan DNA replication origins by tethering the stable ORC2-5 core to chromatin and driving MCM2-7 helicase loading during the M-to-G1 transition (PMID:12909626, PMID:10835370). Its chromatin engagement is directed by an N-terminal BAH domain that reads the repressive histone mark H4K20me2 through an aromatic dimethyl-lysine cage to specify origin occupancy (PMID:22398447), and that also contacts the nucleosome core particle directly to stabilize chromosomal association (PMID:31263106); the BAH domain mediates ORC1 re-association with chromosomes at mitotic exit and supports origin-dependent replication (PMID:17066079, PMID:20595233). ORC1 abundance and chromatin binding are restricted to a narrow window: the protein accumulates in mid-G1, peaks at G1/S, and is then released from chromatin, ubiquitinated, and degraded by the 26S proteasome via SKP2-Cyclin A-CDK2 as cells enter S phase, while ORC2-5 remain constant (PMID:11739726, PMID:12909627, PMID:33761311). During G2/M it is hyperphosphorylated by Cdk1/Cyclin A and excluded from chromatin, and protein phosphatase 1 docks a SLiM in the ORC1 intrinsically disordered region to dephosphorylate it at mitotic exit and license pre-RC assembly (PMID:15199143, PMID:33761311). Beyond replication, ORC1 limits centriole/centrosome copy number through a dedicated CDK-inhibitory domain that suppresses Cyclin E-CDK2 and Cyclin A-CDK2, recruited to centrosomes via Cyclin A through a KXL/Cy motif and PACT domain (PMID:19197067, PMID:22855792, PMID:31309634), and it represses CCNE1 transcription by binding the retinoblastoma protein, SUV39H1, and H3K9me3 (PMID:27458800, PMID:21085491). ORC1 also binds nascent RNA from TSS-proximal origin genes through its IDR to promote its own chromatin release, phosphorylation, and degradation (PMID:37488096). Loss-of-function mutations in ORC1 cause Meier-Gorlin syndrome, disrupting pre-RC formation and origin activation (PMID:21358633, PMID:22855792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Established that ORC1, unlike its partner subunits, is dynamically loaded onto chromatin only in mid-G1 coincident with pre-RC formation, reframing ORC1 as the cell-cycle-regulated trigger of origin licensing rather than a constitutive platform.

    Evidence Chromatin fractionation across cell cycle stages with origin firing assays in hamster cells

    PMID:10835370

    Open questions at the time
    • Did not define the modifications controlling the loading/release switch
    • Mechanism of chromatin recognition unresolved
  2. 2003 High

    Defined ORC1's architectural role: it bridges the stable ORC2-5 complex to chromatin and is required for downstream MCM loading, placing ORC1 upstream in pre-RC assembly.

    Evidence RNAi knockdown plus chromatin fractionation in human cells

    PMID:12909626 PMID:12909627

    Open questions at the time
    • Did not resolve how ORC1 selects specific genomic origins
    • Ubiquitin/degradation machinery not identified
  3. 2002 High

    Revealed that S-phase ORC1 chromatin release is coupled to mono/di-ubiquitination and cytosolic proteasomal degradation, providing the molecular basis for restricting licensing to once per cycle.

    Evidence Chromatin fractionation, ubiquitination detection, and proteasome inhibition with cell-cycle synchronization

    PMID:11739726 PMID:12909627

    Open questions at the time
    • The specific E3 ligase was not identified
    • Coupling between release and ubiquitination left mechanistically open
  4. 2004 Medium

    Connected ORC1 exclusion from mitotic chromatin to Cdk1/Cyclin A-driven hyperphosphorylation, identifying a phospho-switch that keeps ORC1 off chromatin until mitotic exit.

    Evidence Co-IP and CDK inhibitor treatment of metaphase cells with chromatin binding assays; CRM1-dependent nuclear export shown earlier (2001)

    PMID:11716535 PMID:15199143

    Open questions at the time
    • The counteracting phosphatase was not identified
    • Single-lab Co-IP without structural detail of phospho-sites
  5. 2006 High

    Showed the ORC1 BAH domain drives chromosome reassociation at the M-to-G1 transition and origin-dependent replication, separating its chromatin-targeting function from nuclear localization, ORC assembly, and S-phase degradation.

    Evidence BAH domain mutagenesis, EBV oriP replication assay, ChIP, and Co-IP

    PMID:17066079

    Open questions at the time
    • The chromatin ligand recognized by the BAH domain was not defined
    • Did not establish atomic basis of recognition
  6. 2012 High

    Provided the structural and functional basis for origin selection by showing the BAH domain recognizes H4K20me2 via an aromatic cage, with abrogation impairing origin occupancy and cell-cycle progression.

    Evidence Crystal structure of BAH-H4K20me2, mutagenesis, ChIP, and zebrafish rescue

    PMID:22398447

    Open questions at the time
    • Did not address direct nucleosome contacts beyond the histone tail
    • How the mark distribution patterns origin usage genome-wide left open
  7. 2009 High

    Uncovered a replication-independent ORC1 function in restraining centriole/centrosome reduplication via Cyclin A-dependent centrosomal targeting and inhibition of Cyclin E, expanding ORC1 into copy-number control.

    Evidence ORC1 overexpression/depletion, centrosome counting, and immunofluorescence with Cyclin A co-expression

    PMID:19197067

    Open questions at the time
    • The CDK-inhibitory domain was not yet mapped
    • Mechanism of Cyclin E inhibition unresolved
  8. 2012 High

    Mapped ORC1's PACT centrosomal-targeting and CDK-inhibitory domains and linked Meier-Gorlin syndrome mutations to loss of Cyclin E-CDK2 inhibition and centrosome amplification, giving the disease a molecular mechanism.

    Evidence In vitro CDK inhibition assays, domain mutagenesis, centrosome counting, and patient mutation analysis

    PMID:22855792

    Open questions at the time
    • Structural basis of cyclin selectivity not yet resolved
    • Relative contributions of replication vs centrosome defects to disease unclear
  9. 2019 High

    Resolved at atomic resolution how ORC1 selectively recognizes Cyclin A through a KXL motif binding the cyclin binding groove, explaining cyclin specificity of ORC1 regulation.

    Evidence X-ray crystallography of Cyclin A-CDK2 bound to an ORC1 peptide at 2.54 Å

    PMID:31309634

    Open questions at the time
    • Did not address in-cell consequences of disrupting the KXL motif
    • Other cyclin/CDK contacts not structurally defined
  10. 2019 High

    Demonstrated that the Orc1 BAH domain contacts the nucleosome core particle without discriminating H4K16 acetylation state, allowing engagement of both hetero- and euchromatin, and that this contact is required for genome stability functions.

    Evidence Crystal structure of Orc1-BAH–nucleosome complex, acetylation-variant binding assays, and in vivo meiotic rDNA assays in yeast

    PMID:31263106

    Open questions at the time
    • Generalization of nucleosome contacts to human origin selection not directly tested
    • Interplay with the H4K20me2 mark not reconciled
  11. 2016 High

    Placed ORC1 in transcriptional repression of the cell-cycle gene CCNE1 by binding RB, SUV39H1, and H3K9me3, with CDC6 antagonizing this repression, integrating origin licensing factors into G1/S transcriptional control.

    Evidence Co-IP, ChIP, reporter assays, and ORC1/CDC6 knockdown/overexpression; complemented by direct RB-ORC1 binding shown in 2010

    PMID:21085491 PMID:27458800

    Open questions at the time
    • Generality across other cell-cycle promoters not established
    • How transcriptional and replication roles are temporally coordinated unclear
  12. 2021 High

    Resolved the phospho-regulatory logic by showing SLiMs in the ORC1 IDR govern phase-specific CDC6 interaction, SKP2-Cyclin A-CDK2-driven destruction in late G1, and direct PP1 binding that dephosphorylates ORC1 at mitotic exit to enable pre-RC assembly.

    Evidence Co-IP, domain mutagenesis, in vitro binding and ubiquitination assays with cell-cycle synchronization

    PMID:33761311

    Open questions at the time
    • Full set of SLiM-binding partners not exhaustively mapped
    • Structural detail of the PP1-SLiM interface not resolved
  13. 2023 High

    Identified an RNA-binding activity in the ORC1 IDR for nascent transcripts from origin-proximal TSSs that promotes ORC1 chromatin release, phosphorylation, and degradation, coupling transcription to origin activation.

    Evidence RNA immunoprecipitation, RNA-binding mutagenesis, nascent strand sequencing, and phosphorylation analysis

    PMID:37488096

    Open questions at the time
    • Sequence/structural determinants of RNA recognition not defined
    • How RNA binding mechanistically triggers phosphorylation unresolved
  14. 2018 High

    Genetically dissociated ORC1 requirement between division modes, showing it is essential for mitotic divisions but dispensable for endoreduplication in polyploid trophoblasts and hepatocytes, revealing an ORC1-independent licensing route in polyploid genomes.

    Evidence Conditional knockout mice with tissue-specific Cre ablation and DNA content analysis

    PMID:29967292

    Open questions at the time
    • The ORC1-independent licensing mechanism was not identified
    • Whether other ORC subunits substitute is unknown
  15. 2024 Medium

    Extended ORC1 function to viral chromatin silencing, showing it is enriched at the HIV-1 LTR where it recruits DNMT1 and HDAC1/2 and promotes repressive histone marks via phase-separation-dependent recruitment to enforce latency.

    Evidence CRISPR affinity purification, ChIP, knockdown, LLPS assays, and primary CD4+ T cell experiments

    PMID:39082875

    Open questions at the time
    • Single-lab study; reciprocal validation limited
    • Relationship between LLPS and origin functions unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ORC1's multiple regulatory inputs — H4K20me2/nucleosome reading, RNA binding, phospho/ubiquitin cycling, and phase separation — are integrated to choose specific origins genome-wide, and what mediates ORC1-independent replication in polyploid cells, remain unresolved.
  • No unified model linking chromatin, RNA, and modification inputs to origin choice
  • ORC1-independent endoreduplication machinery unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 3 GO:0005815 microtubule organizing center 3 GO:0005829 cytosol 3
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-4839726 Chromatin organization 3 R-HSA-69306 DNA Replication 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 2
Partners
CCNA2CDC6CDK2HBO1MYCORC2RB1SUV39H1
Complex memberships
Origin Recognition Complex (ORC1-5)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 The BAH domain of human ORC1 specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2) through a dynamic aromatic dimethyl-lysine-binding cage. Abrogating this interaction impairs ORC1 occupancy at replication origins, ORC chromatin loading, and cell-cycle progression. This property is conserved across metazoan ORC1 proteins. Crystal structure of BAH domain bound to H4K20me2 peptide; active-site mutagenesis; chromatin immunoprecipitation; zebrafish morphant rescue experiments Nature High 22398447
1999 Human ORC1 protein physically interacts with histone acetyltransferase HBO1 (a MYST family member). A fraction of HBO1 associates with ORC1 in human cell extracts, and the complex possesses histone H3 and H4 acetyltransferase activities. Co-immunoprecipitation from human cell extracts; biochemical fractionation; HAT activity assay The Journal of biological chemistry Medium 10438470
2001 MCM2 also interacts directly with HBO1, with the N-terminal domain of MCM2 binding the C2HC zinc finger of HBO1. This interaction with ORC1 and MCM2 suggests HBO1-associated HAT activity plays a direct role in DNA replication. Yeast two-hybrid screen; in vitro binding assay; reverse two-hybrid suppressor mutagenesis; co-immunoprecipitation The Journal of biological chemistry Medium 11278932
1998 Human CDC6 (hCdc18) associates physically with human ORC1 protein and with cyclin-CDKs. CDC6 is nuclear in G1 and selectively eliminated from the nucleus at S phase onset, supporting its role in replication initiation regulation. Two-hybrid screen; co-immunoprecipitation; cell cycle fractionation and immunofluorescence Molecular and cellular biology Medium 9566895
2011 Mutations in ORC1 disrupt pre-replicative complex formation and origin activation, perturb S-phase entry and progression, demonstrating ORC1's essential role in replication licensing. Orc1 depletion in zebrafish markedly reduces body size during embryonic growth. Patient mutation analysis; pre-RC assembly assay; BrdU incorporation/flow cytometry; zebrafish morpholino knockdown Nature genetics High 21358633
2002 Mammalian ORC1 is selectively released from chromatin as cells enter S phase, converted to a mono- or di-ubiquitinated form, and then deubiquitinated and re-bound to chromatin during the M-to-G1 transition. Orc2 remains tightly bound to chromatin throughout the cell cycle and is not ubiquitinated. ORC1 degradation by the 26S proteasome occurs only when released into the cytosol. Chromatin fractionation; immunoblotting; cell cycle synchronization; proteasome inhibitor treatment Molecular and cellular biology High 11739726
2003 Human ORC1 levels oscillate during the cell cycle: accumulating in mid-G1, peaking at G1/S, and decreasing in S phase via 26S proteasome-dependent degradation. Other ORC subunits (ORC2-5) remain at constant levels throughout the cell cycle. Immunoblotting with specific antibody; cell cycle synchronization; proteasome inhibitor (MG132) treatment; cell lines with ectopic ORC1 expression The Journal of biological chemistry High 12909627
2003 ORC2-5 form a stable complex throughout the cell cycle and associate with ORC1 in G1. ORC1 tethers ORC2-5 to nuclear structures, and RNAi-mediated ORC1 reduction blocks MCM protein loading onto chromatin. Chromatin fractionation (nuclease-soluble and -insoluble); RNAi knockdown; immunoblotting; cell cycle synchronization The Journal of biological chemistry High 12909626
2004 Orc1 selectively associates with Cdk1/cyclin A during G2/M phase, leading to Orc1 hyperphosphorylation that prevents it from binding chromatin. Inhibition of CDK activity in metaphase cells results in rapid Orc1 binding to chromatin. Co-immunoprecipitation; kinase inhibitor treatment of metaphase cells; chromatin binding assay Molecular and cellular biology Medium 15199143
2006 The BAH domain of human Orc1 facilitates reassociation of Orc1 with chromosomes during the M-to-G1 transition and is required for ORC binding at Epstein-Barr virus oriP and stimulation of oriP-dependent DNA replication. The BAH domain is not required for nuclear localization, association with other ORC subunits, or S-phase degradation. BAH domain mutagenesis; plasmid DNA replication assay; chromatin immunoprecipitation; co-immunoprecipitation The EMBO journal High 17066079
2009 Orc1 controls centriole and centrosome copy number in human cells independent of its role in DNA replication. Cyclin A promotes Orc1 localization to centrosomes, where Orc1 prevents Cyclin E-dependent reduplication of centrioles and centrosomes. Orc1 overexpression/depletion; centrosome counting; immunofluorescence localization; cyclin A co-expression experiments Science (New York, N.Y.) High 19197067
2012 Orc1 harbors a PACT centrosome-targeting domain and a CDK inhibitory domain that differentially inhibits Cyclin E-CDK2 and Cyclin A-CDK2 kinase activities via distinct mechanisms. Meier-Gorlin syndrome mutations in ORC1 disrupt Cyclin E-CDK2 inhibition and permit centrosome reduplication. The Cy motif is required for Cyclin A binding and Cyclin A-CDK2 inhibition. In vitro CDK inhibition assay; domain mutagenesis; centrosome counting; co-immunoprecipitation; patient mutation analysis Genes & development High 22855792
2021 Multiple short linear protein motifs (SLiMs) within intrinsically disordered regions (IDRs) of ORC1 and CDC6 mediate cell cycle phase-dependent protein-protein interactions. An ORC1 IDR domain is required for ORC1-CDC6 interaction in G1 but prevents it during mitosis. SKP2-Cyclin A-CDK2 drives ORC1 destruction in late G1. Protein phosphatase 1 binds directly to a SLiM in the ORC1 IDR, causing ORC1 dephosphorylation upon mitotic exit to promote pre-RC assembly. Co-immunoprecipitation; domain mutagenesis; cell cycle synchronization; in vitro binding assays; ubiquitination assays Molecular cell High 33761311
2016 ORC1 represses Cyclin E gene (CCNE1) transcription by binding to the retinoblastoma protein (RB), the histone methyltransferase SUV39H1, and the repressive H3K9me3 mark. In contrast, CDC6 binds Cyclin E-CDK2 and removes RB from ORC1, thereby hyper-activating CCNE1 transcription. Co-immunoprecipitation; ChIP; reporter assays; ORC1/CDC6 knockdown/overexpression eLife High 27458800
2010 Retinoblastoma protein (Rb) binds directly to ORC1 (the largest subunit of ORC) in vitro and in cells; this interaction is competitive with Rb-E2F1 binding. Rb and E2F1 bind replication origins in a cell-cycle-regulated manner, and displacement of Rb-bound ORC1 by E2F1 marks progression toward the G1/S border. GST pulldown; co-immunoprecipitation; chromatin immunoprecipitation PloS one Medium 21085491
2006 Mono-ubiquitylation and hyperphosphorylation of Orc1 during S and G2/M phases, respectively, cause Orc1 accumulation in the cytoplasm. In the absence of these modifications, Orc1 rapidly induces p53-independent apoptosis and accumulates perinuclearly. Co-expression with Orc2 prevents apoptosis and restores uniform nuclear localization of Orc1. Transient expression of Orc1 mutants; immunofluorescence localization; apoptosis assays; co-expression with Orc2 Journal of cell science Medium 16537645
2001 Overexpression of viral cyclin or cyclin A causes CRM1-dependent nuclear export of human Orc1 to the cytoplasm, dependent on phosphorylation of CDK target sites in Orc1. Immunofluorescence; CRM1 inhibitor (leptomycin B) treatment; site-directed mutagenesis of CDK phosphorylation sites Experimental cell research Medium 11716535
2000 ORC1 directly binds the N-terminal region of c-Myc (responsible for gene silencing) in a complex containing other ORC subunits and Max. ORC1 inhibits E-box-dependent transcription by competitively binding the C-terminal region of c-Myc with SNF5, a component of the SWI/SNF chromatin remodeling complex. Co-immunoprecipitation in vivo and in vitro; reporter gene assay for E-box-dependent transcription; competitive binding assay Genes to cells : devoted to molecular & cellular mechanisms Medium 10886373
2005 Drosophila ORC1 is degraded at the end of M phase by the APC activated by Fzr/Cdh1 through a novel sequence called the O-box, which is necessary and sufficient for Fzr/Cdh1-dependent polyubiquitylation in vitro and degradation in vivo. The O-box is distinct from the D-box and KEN-box. In vitro polyubiquitylation assay; in vivo degradation assay; mutagenesis of the O-box; APC activation experiments Genes & development High 16195415
2015 ORC1 re-localizes to condensing chromatin during early mitosis and the initial binding to mitotic chromosomes requires C-terminal amino acid sequences similar to mitotic chromosome-binding sequences in FOXA1. Orc1 depletion causes concomitant loss of MCM2-7 helicase proteins on chromatin, indicating Orc1 is required for pre-RC assembly. Live cell imaging of fluorescently tagged Orc1; domain mutagenesis; chromatin fractionation after Orc1 depletion The Journal of biological chemistry Medium 25784553
2010 The Orc1 BAH domain in budding yeast is required for stable chromosomal association of ORC and contributes to ORC binding at most yeast origins; its role in replication is separable from its role in transcriptional silencing. Genome-wide ORC ChIP-chip in wild-type vs orc1bahΔ cells; plasmid and chromosomal replication assays; genetic silencing assays Genes & development High 20595233
2019 Crystal structure of the yeast Orc1 BAH domain bound to the nucleosome core particle reveals that Orc1 does not discriminate between H4K16-acetylated and non-acetylated states (unlike Sir3), enabling interaction with both hetero- and euchromatin. Direct nucleosome interactions are essential for Orc1 to maintain rDNA border integrity during meiosis. Crystal structure of Orc1-BAH–nucleosome complex; binding assays with acetylation-state variants; in vivo meiotic rDNA assays Nature communications High 31263106
2019 Crystal structure of Cyclin A-CDK2 bound to an ORC1-derived peptide at 2.54 Å resolution reveals that ORC1 interacts with the cyclin binding groove (CBG) of Cyclin A via a KXL motif, with an arginine flanking the KXL motif inserting into a neighboring acidic pocket. This structural basis explains ORC1's specific recognition of Cyclin A over other cyclins. X-ray crystallography; structural and sequence analysis Protein science : a publication of the Protein Society High 31309634
2015 The ORC1 R105Q Meier-Gorlin Syndrome mutation reduces the hORC1 BAH domain binding affinity for nucleosomal DNA, leading to impaired ORC1-BAH–nucleosome interaction, which likely compromises replication origin recognition. Binding assays with chemically modified H4Kc20me2 nucleosome; mutagenesis; fluorescence polarization ACS chemical biology Medium 25689043
2018 ORC1 is essential for mitotic cell divisions in mice but dispensable for endoreduplication in polyploid trophoblasts and hepatocytes, demonstrating that DNA replication of mammalian polyploid genomes uses a distinct ORC1-independent mechanism. Conditional knockout (LoxP/Cre) mice; tissue-specific Cre-mediated ORC1 ablation; DNA content analysis; developmental phenotyping Genes & development High 29967292
2010 Cyclin A interacts with both MCM5 and Orc1 through its centrosomal localization sequence (CLS) in a Cdk-independent manner, recruiting these replication factors to centrosomes. The hydrophobic patch MRAIL is contained within the CLS but binding of MCM5 and Orc1 does not require a wild-type hydrophobic patch. Co-immunoprecipitation; domain mutagenesis; centrosome reduplication assay in CHO cells Journal of cell science Medium 20663915
2000 Hamster Orc1 is easily eluted from chromatin during mitosis and early G1 (when functional ORCs are absent) but becomes stably bound in mid-G1 concomitant with pre-replication complex appearance. Orc2 by contrast remains stably chromatin-bound throughout the cell cycle. Chromatin fractionation at defined cell cycle stages; DNA replication origin firing assay; immunoblotting The EMBO journal High 10835370
2023 ORC1 binds RNAs transcribed from genes with origins at their transcription start sites. RNA binding resides in ORC1's intrinsically disordered region. RNA depletion or use of an ORC1 RNA-binding mutant results in inefficient origin activation, linked to impaired ORC1 chromatin release. RNA binding promotes ORC1 phosphorylation and subsequent degradation. RNA immunoprecipitation; ORC1 RNA-binding mutagenesis; origin firing assay (nascent strand sequencing); phosphorylation analysis Nature communications High 37488096
2024 ORC1 is enriched on the HIV-1 LTR promoter, where it recruits repressive epigenetic factors including DNMT1, HDAC1/2, and histone modifiers promoting H3K9me3 and H3K27me3 marks, thereby facilitating HIV-1 latency. ORC1 displays liquid-liquid phase separation (LLPS) properties important for its recruitment to the HIV-1 promoter. CRISPR affinity purification; ChIP; ORC1 knockdown; LLPS assay; primary CD4+ T cell experiments Journal of virology Medium 39082875
1999 In S. cerevisiae, a 17-amino-acid segment of Sir1p is required for recognition of the HMR-E silencer and for interaction with Orc1p, establishing that Sir1 is recruited to silencers indirectly through Orc1. Genetic screen for SIR1 alleles defective in silencer recognition; two-hybrid interaction assay; tethering experiments Genetics Medium 9872946
2005 Mouse Orc1 exists in two splice variants: Orc1A (full-length) and Orc1B (lacking 35 amino acids in exon 5). Orc1A localizes to the nucleus via the 35 amino acid segment, while Orc1B remains exclusively cytoplasmic. Orc1A is degraded by the ubiquitin-proteasome pathway, whereas Orc1B is degraded via a proteasome-independent mechanism. Cloning and sequencing of splice variants; subcellular localization by immunofluorescence; domain fusion with beta-galactosidase; proteasome inhibitor treatment The Journal of biological chemistry Medium 15634681
2002 AlF-C1 and AlF-C2 (transcriptional repressors of the rat aldolase B gene) directly bind Orc1 at the aldB origin/promoter. Deletion analysis identified separate domains in AlF-C2 for DNA binding and Orc1 binding, and a conserved protein-interaction domain in mammalian but not Drosophila or yeast Orc1. GST pulldown; deletion analysis; ChIP Nucleic acids research Medium 12466545
2025 The BAH domain of yeast Orc1, which recruits Sir1 to Orc1-bound silencers, ceases to bind Sir1 in the presence of nucleosome, suggesting that nucleosome association by the BAH domain is mutually exclusive with Sir1 binding. Biochemical binding assays (BAH domain with Sir1 and nucleosome); structural dissection of BAH domain determinants bioRxivpreprint Medium bio_10.1101_2025.03.14.643217

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome. Nature 285 22398447
1999 Histone acetyltransferase HBO1 interacts with the ORC1 subunit of the human initiator protein. The Journal of biological chemistry 263 10438470
1998 Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. Molecular and cellular biology 220 9566895
2011 Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nature genetics 171 21358633
2001 Replication factors MCM2 and ORC1 interact with the histone acetyltransferase HBO1. The Journal of biological chemistry 162 11278932
2012 Genome-wide mapping of human DNA-replication origins: levels of transcription at ORC1 sites regulate origin selection and replication timing. Genome research 139 23187890
1996 Expression of the HsOrc1 gene, a human ORC1 homolog, is regulated by cell proliferation via the E2F transcription factor. Molecular and cellular biology 137 8943353
2007 Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex. Science (New York, N.Y.) 129 17761879
2009 Orc1 controls centriole and centrosome copy number in human cells. Science (New York, N.Y.) 121 19197067
2001 In vivo interactions of archaeal Cdc6/Orc1 and minichromosome maintenance proteins with the replication origin. Proceedings of the National Academy of Sciences of the United States of America 115 11562464
2002 Mammalian Orc1 protein is selectively released from chromatin and ubiquitinated during the S-to-M transition in the cell division cycle. Molecular and cellular biology 105 11739726
1996 The ORC1 homolog orp1 in fission yeast plays a key role in regulating onset of S phase. Genes & development 102 8895665
2003 The ORC1 cycle in human cells: I. cell cycle-regulated oscillation of human ORC1. The Journal of biological chemistry 94 12909627
1999 E2F mediates developmental and cell cycle regulation of ORC1 in Drosophila. The EMBO journal 82 10228158
1999 A region of the Sir1 protein dedicated to recognition of a silencer and required for interaction with the Orc1 protein in saccharomyces cerevisiae. Genetics 77 9872946
2006 The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo. The EMBO journal 74 17066079
2003 The ORC1 cycle in human cells: II. Dynamic changes in the human ORC complex during the cell cycle. The Journal of biological chemistry 73 12909626
2019 Up-regulated lncRNA XIST contributes to progression of cervical cancer via regulating miR-140-5p and ORC1. Cancer cell international 71 30858762
2004 Role for Cdk1 (Cdc2)/cyclin A in preventing the mammalian origin recognition complex's largest subunit (Orc1) from binding to chromatin during mitosis. Molecular and cellular biology 71 15199143
2000 Selective instability of Orc1 protein accounts for the absence of functional origin recognition complexes during the M-G(1) transition in mammals. The EMBO journal 69 10835370
2010 The conserved bromo-adjacent homology domain of yeast Orc1 functions in the selection of DNA replication origins within chromatin. Genes & development 66 20595233
2008 Differential association of Orc1 and Sir2 proteins to telomeric domains in Plasmodium falciparum. Journal of cell science 64 18525026
2009 Trypanosome prereplication machinery contains a single functional orc1/cdc6 protein, which is typical of archaea. Eukaryotic cell 56 19717742
2010 The cyclin A centrosomal localization sequence recruits MCM5 and Orc1 to regulate centrosome reduplication. Journal of cell science 54 20663915
2006 Ligand-controlled interaction of histone acetyltransferase binding to ORC-1 (HBO1) with the N-terminal transactivating domain of progesterone receptor induces steroid receptor coactivator 1-dependent coactivation of transcription. Molecular endocrinology (Baltimore, Md.) 54 16645042
2012 Meier-Gorlin syndrome mutations disrupt an Orc1 CDK inhibitory domain and cause centrosome reduplication. Genes & development 53 22855792
2012 Trypanosoma brucei Orc1 is essential for nuclear DNA replication and affects both VSG silencing and VSG switching. Molecular microbiology 51 23216794
1999 The essential role of Saccharomyces cerevisiae CDC6 nucleotide-binding site in cell growth, DNA synthesis, and Orc1 association. The Journal of biological chemistry 51 10075735
2004 Biochemical characterization of Cdc6/Orc1 binding to the replication origin of the euryarchaeon Methanothermobacter thermoautotrophicus. Nucleic acids research 50 15358831
2021 Multiple, short protein binding motifs in ORC1 and CDC6 control the initiation of DNA replication. Molecular cell 48 33761311
2012 Identification of ORC1/CDC6-interacting factors in Trypanosoma brucei reveals critical features of origin recognition complex architecture. PloS one 46 22412905
2005 A novel motif governs APC-dependent degradation of Drosophila ORC1 in vivo. Genes & development 46 16195415
2011 The Cdc45·Mcm2-7·GINS protein complex in trypanosomes regulates DNA replication and interacts with two Orc1-like proteins in the origin recognition complex. The Journal of biological chemistry 45 21799014
2010 Transcriptional silencing functions of the yeast protein Orc1/Sir3 subfunctionalized after gene duplication. Proceedings of the National Academy of Sciences of the United States of America 45 20974972
2006 Ubiquitylation, phosphorylation and Orc2 modulate the subcellular location of Orc1 and prevent it from inducing apoptosis. Journal of cell science 44 16537645
2015 Orc1 Binding to Mitotic Chromosomes Precedes Spatial Patterning during G1 Phase and Assembly of the Origin Recognition Complex in Human Cells. The Journal of biological chemistry 42 25784553
2011 Molecular determinants of origin discrimination by Orc1 initiators in archaea. Nucleic acids research 38 21227921
2000 ORC1 interacts with c-Myc to inhibit E-box-dependent transcription by abrogating c-Myc-SNF5/INI1 interaction. Genes to cells : devoted to molecular & cellular mechanisms 36 10886373
2018 An Orc1/Cdc6 ortholog functions as a key regulator in the DNA damage response in Archaea. Nucleic acids research 32 29878182
2019 Structure and function of the Orc1 BAH-nucleosome complex. Nature communications 31 31263106
2009 Archaeal eukaryote-like Orc1/Cdc6 initiators physically interact with DNA polymerase B1 and regulate its functions. Proceedings of the National Academy of Sciences of the United States of America 31 19416914
2012 The role of N-terminus of Plasmodium falciparum ORC1 in telomeric localization and var gene silencing. Nucleic acids research 30 22379140
2007 Genomewide and biochemical analyses of DNA-binding activity of Cdc6/Orc1 and Mcm proteins in Pyrococcus sp. Nucleic acids research 29 17452353
2021 The Synergistic Anti-Tumor Activity of EZH2 Inhibitor SHR2554 and HDAC Inhibitor Chidamide through ORC1 Reduction of DNA Replication Process in Diffuse Large B Cell Lymphoma. Cancers 28 34503063
2016 Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. eLife 26 27458800
2006 Binding of AlF-C, an Orc1-binding transcriptional regulator, enhances replicator activity of the rat aldolase B origin. Molecular and cellular biology 24 16982680
2000 Molecular cloning and characterization of a plant homologue of the origin recognition complex 1 (ORC1). Plant science : an international journal of experimental plant biology 23 10996242
1996 Characterization of a novel CDC gene (ORC1) partly homologous to CDC6 of Saccharomyces cerevisiae. Molecular biology of the cell 23 8868469
2010 Interaction of the retinoblastoma protein with Orc1 and its recruitment to human origins of DNA replication. PloS one 22 21085491
2008 Expression and subcellular localization of ORC1 in Leishmania major. Biochemical and biophysical research communications 22 18680728
2001 Cyclin-mediated export of human Orc1. Experimental cell research 22 11716535
2002 Functional domains involved in the interaction between Orc1 and transcriptional repressor AlF-C that bind to an origin/promoter of the rat aldolase B gene. Nucleic acids research 21 12466545
2018 Endoreduplication of the mouse genome in the absence of ORC1. Genes & development 20 29967292
1996 Disruption of re-replication control by overexpression of human ORC1 in fission yeast. The Journal of biological chemistry 19 8955071
2012 Archaeal orc1/cdc6 proteins. Sub-cellular biochemistry 18 22918580
2023 ORC1 binds to cis-transcribed RNAs for efficient activation of replication origins. Nature communications 16 37488096
2007 Divergent functions of multiple eukaryote-like Orc1/Cdc6 proteins on modulating the loading of the MCM helicase onto the origins of the hyperthermophilic archaeon Sulfolobus solfataricus P2. Biochemical and biophysical research communications 16 17673179
2005 Biochemical characterization of two Cdc6/ORC1-like proteins from the crenarchaeon Sulfolobus solfataricus. Extremophiles : life under extreme conditions 16 16179962
2009 Localized melting of duplex DNA by Cdc6/Orc1 at the DNA replication origin in the hyperthermophilic archaeon Pyrococcus furiosus. Extremophiles : life under extreme conditions 15 19787415
2010 Cdc6/Orc1 from Pyrococcus furiosus may act as the origin recognition protein and Mcm helicase recruiter. Genes to cells : devoted to molecular & cellular mechanisms 13 20384788
2014 ORC1/CDC6 and MCM7 distinct associate with chromatin through Trypanosoma cruzi life cycle. Molecular and biochemical parasitology 12 24681203
2013 Characterization of the replication initiator Orc1/Cdc6 from the Archaeon Picrophilus torridus. Journal of bacteriology 12 24187082
2007 Three eukaryote-like Orc1/Cdc6 proteins functionally interact and mutually regulate their activities of binding to the replication origin in the hyperthermophilic archaeon Sulfolobus solfataricus P2. Biochemical and biophysical research communications 12 17825793
2020 DEFA1B inhibits ZIKV replication and retards cell cycle progression through interaction with ORC1. Life sciences 11 33075374
2015 A Meier-Gorlin syndrome mutation impairs the ORC1-nucleosome association. ACS chemical biology 10 25689043
2008 RNA interference targeting ORC1 gene suppresses the proliferation of vascular smooth muscle cells in rats. Experimental and molecular pathology 9 18499104
2022 Origin recognition complex subunit 1 (ORC1) augments malignant behaviors of lung adenocarcinoma cells via targeting Wnt signaling. Bioengineered 8 36700467
2016 Ndt80 activates the meiotic ORC1 transcript isoform and SMA2 via a bi-directional middle sporulation element in Saccharomyces cerevisiae. RNA biology 8 27362276
2005 Novel splicing variant of mouse Orc1 is deficient in nuclear translocation and resistant for proteasome-mediated degradation. The Journal of biological chemistry 8 15634681
2003 Characterisation of a sexual stage-specific gene encoding ORC1 homologue in the human malaria parasite Plasmodium falciparum. Parasitology international 8 12543146
2023 Origin recognition complex subunit 1(ORC1) is a potential biomarker and therapeutic target in cancer. BMC medical genomics 7 37833711
2019 Structural basis for the ORC1-Cyclin A association. Protein science : a publication of the Protein Society 7 31309634
2009 Novel insights into the plant histone code: lessons from ORC1. Epigenetics 7 19483463
2012 A highly basic sequence at the N-terminal region is essential for targeting the DNA replication protein ORC1 to the nucleus in Leishmania donovani. Microbiology (Reading, England) 6 22575896
1998 Mouse homolog of the yeast origin recognition complex subunit ORC1 and chromosomal localization of the cognate mouse gene Orc1. Molecular & general genetics : MGG 6 9862484
2024 ORC1 enhances repressive epigenetic modifications on HIV-1 LTR to promote HIV-1 latency. Journal of virology 5 39082875
2022 Dissection of Functional Domains of Orc1-2, the Archaeal Global DNA Damage-Responsive Regulator. International journal of molecular sciences 5 36498936
2021 SLiMs in intrinsically disordered protein regions regulate the cell cycle dynamics of ORC1-CDC6 interaction and pre-replicative complex assembly. Molecular cell 5 33961774
2020 Active transcription and Orc1 drive chromatin association of the AAA+ ATPase Pch2 during meiotic G2/prophase. PLoS genetics 5 32569318
2011 Localization of ORC1 during the cell cycle in human leukemia cells. Analytical cellular pathology (Amsterdam) 5 22045277
2008 The regulatory function of N-terminal AAA+ ATPase domain of eukaryote-like archaeal Orc1/Cdc6 protein during DNA replication initiation. Archives of biochemistry and biophysics 4 18237540
2024 Up-regulated ORC1 promotes lung adenocarcinoma by inhibiting ferroptosis via SLC7A11 dependent pathway. Heliyon 3 38756571
2020 A novel 1p33p32.2 deletion involving SCP2, ORC1, and DAB1 genes in a patient with craniofacial dysplasia, short stature, developmental delay, and leukoencephalopathy: A case report. Medicine 3 33157955
2012 An orc1 allele with a mutated APC motif is female sterile with amplification defects. Cell cycle (Georgetown, Tex.) 3 22801552
2011 Function of the origin recognition complex 1 (ORC1) outside DNA replication in Drosophila. Cell cycle (Georgetown, Tex.) 3 22071690
2025 IGF2BP1/ORC1 Axis Influences Nonsmall Cell Lung Cancer Progression via m6A Methylation Modification. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 40948373
2025 Control of the archaeal DNA damage-responsive pathway by phosphorylation of Orc1-2, the global regulator in Saccharolobus islandicus. Nucleic acids research 2 40973452
2022 The DNA replication protein Orc1 from the yeast Torulaspora delbrueckii is required for heterochromatin formation but not as a silencer-binding protein. Genetics 2 35894940
2022 Sulfolobus islandicus Employs Orc1-2-Mediated DNA Damage Response in Defense against Infection by SSV2. Journal of virology 2 36448807
2021 Archaeal Orc1 protein interacts with T-rich single-stranded DNA. BMC research notes 2 34281605
2010 Characterization of physical and functional interactions between eukaryote-like Orc1/Cdc6 proteins and Y-family DNA polymerase in the hyperthermophilic archaeon Sulfolobus solfataricus. Biochemical and biophysical research communications 2 20457125
2007 Regulation of the functional interactions between archaeal eukaryote-like Cdc6/Orc1 proteins on the replication origin by two different mechanisms. Biochemical and biophysical research communications 1 18155660
2026 Integration of ploidy, Orc1/Cdc6 homolog function, and lysine acetylation with phosphate limitation and UV stress responses of Haloferax volcanii. Extremophiles : life under extreme conditions 0 41667842
2026 An Orc1 initiator-specific motif (ISM)-related region limits ORC-ssDNA binding and promotes replication origin specificity in budding yeast. Frontiers in microbiology 0 42100701
2022 Identification, expression and subcellular localization of Orc1 in the microsporidian Nosema bombycis. Gene 0 35609797
2007 Functional differentiation and cooperative interaction between two eukaryote-like archaeal Orc1/Cdc6 proteins on the replication origin. Biochemical and biophysical research communications 0 17964284

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