Affinage

ORC1

Origin recognition complex subunit 1 · UniProt Q13415

Length
861 aa
Mass
97.3 kDa
Annotated
2026-04-29
98 papers in source corpus 35 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ORC1 is the largest and sole cell-cycle-regulated subunit of the origin recognition complex, functioning as a central integrator of DNA replication licensing, centrosome copy number control, and transcriptional repression. Its N-terminal BAH domain recognizes H4K20me2 on nucleosomes to target ORC to replication origins, where ORC1 recruits CDC6 via intrinsically disordered region-embedded short linear motifs in G1, enabling MCM2-7 helicase loading and pre-replication complex assembly; ORC1 protein levels oscillate through the cell cycle via CDK-dependent phosphorylation that prevents chromatin binding in mitosis, SCF-SKP2-mediated ubiquitination and proteasomal degradation in S phase, and PP1-mediated dephosphorylation upon mitotic exit that restores ORC1 stability and chromatin association (PMID:22398447, PMID:33761311, PMID:12909627, PMID:15199143). Independently of replication, ORC1 localizes to centrosomes via Cyclin A and a PACT domain, where its CDK inhibitory domain suppresses Cyclin E-CDK2 to prevent centriole reduplication, and it represses CCNE1 transcription by cooperating with RB and SUV39H1 to establish H3K9me3 at E2F target promoters (PMID:19197067, PMID:22855792, PMID:27458800). Mutations in the ORC1 BAH domain or CDK inhibitory domain cause Meier-Gorlin syndrome, a primordial dwarfism disorder, through combined defects in replication licensing and centrosome duplication (PMID:21358633, PMID:22855792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1996 High

    Establishing ORC1 as an essential replication initiation factor: fission yeast Orp1 was shown to be required for S-phase onset and to form complexes with Cdc18 and MCM homologs, while human ORC1 transcription was found to be E2F-regulated and CDK-dependent, linking ORC1 expression to cell-cycle commitment.

    Evidence Temperature-sensitive and null mutant analysis with FACS in S. pombe; promoter-reporter assays with E2F overexpression and CDK inhibition in human cells

    PMID:8895665 PMID:8943353

    Open questions at the time
    • Mechanism of ORC1 recruitment to specific origins in metazoans was unknown
    • Whether ORC1 protein levels were regulated post-translationally was not addressed
  2. 1999 High

    Defining the ORC1-CDC6 interaction as the key step in pre-RC assembly: CDC6/Cdc6 was shown to physically associate with ORC1/Orc1 in an ATP-dependent manner, and this interaction was required for MCM loading onto origins, while ORC1 was also linked to chromatin acetylation through its interaction with the HAT HBO1.

    Evidence Co-IP plus ATP-binding mutagenesis plus chromatin fractionation in yeast; reciprocal Co-IP from human cells with HAT activity assays

    PMID:10075735 PMID:10438470 PMID:9566895

    Open questions at the time
    • How ORC1 recognizes specific chromatin marks at origins was unknown
    • Whether HBO1 activity is functionally required for ORC-dependent replication was untested
  3. 2002 High

    Revealing that ORC1 is the uniquely regulated ORC subunit: ORC1 was shown to be selectively released from chromatin in S phase, ubiquitinated, and degraded by the proteasome, while other ORC subunits remain constant — establishing cell-cycle oscillation of ORC1 as the principal mechanism preventing re-replication in mammalian cells.

    Evidence Chromatin fractionation, ubiquitination assays, proteasome inhibitor treatment, and cell-cycle synchronization in multiple mammalian cell lines

    PMID:11739726 PMID:12909627

    Open questions at the time
    • The E3 ubiquitin ligase responsible for mammalian ORC1 degradation was not identified
    • Whether ORC1 degradation is sufficient to prevent re-replication was unclear
  4. 2004 High

    Identifying CDK1-Cyclin A phosphorylation as the mitotic block to ORC1 chromatin binding: Cdk1/Cyclin A was found to associate with and hyperphosphorylate ORC1 during G2/M, and CDK inhibition in metaphase rapidly restored ORC1 chromatin association, explaining how mitotic cells prevent premature origin licensing.

    Evidence Reciprocal Co-IP, phosphorylation assays, CDK inhibitor treatment in metaphase-arrested cells, chromatin fractionation

    PMID:15199143

    Open questions at the time
    • Which specific phosphorylation sites block chromatin binding was not mapped
    • How ORC1 is dephosphorylated upon mitotic exit was unknown
  5. 2006 High

    Demonstrating the BAH domain as the chromatin-targeting module of ORC1: the BAH domain was shown to be required for ORC1 reassociation with chromosomes at M/G1 transition and for stimulating origin-dependent DNA replication, while being dispensable for nuclear localization and ORC subunit interactions.

    Evidence BAH domain mutagenesis combined with EBV oriP replication assay and chromatin fractionation

    PMID:17066079

    Open questions at the time
    • The specific histone modification recognized by the BAH domain was not yet identified
    • Whether the BAH domain binds nucleosomes directly was untested
  6. 2009 High

    Uncovering a replication-independent role for ORC1 in centrosome copy number control: ORC1 was found to localize to centrosomes via Cyclin A and to prevent Cyclin E-dependent centriole reduplication, establishing a bifunctional role for ORC1 in both genome and centrosome duplication.

    Evidence siRNA knockdown, overexpression, centrosome counting by immunofluorescence, Co-IP with cyclins in human cells

    PMID:19197067

    Open questions at the time
    • The molecular mechanism by which ORC1 inhibits Cyclin E-CDK2 at centrosomes was unknown
    • Whether centrosome defects contribute to disease phenotypes was untested
  7. 2012 High

    Resolving the molecular basis of ORC1-chromatin recognition and connecting both ORC1 functions to Meier-Gorlin syndrome: the BAH domain crystal structure revealed a dimethyl-lysine cage recognizing H4K20me2, while domain mapping identified a PACT centrosome-targeting domain and a CDK inhibitory domain that differentially inhibits Cyclin E-CDK2; disease mutations disrupted both chromatin recognition and CDK inhibition.

    Evidence Crystal structure of BAH-H4K20me2 complex; domain mapping with kinase assays; centrosome reduplication assays; patient mutation analysis; zebrafish rescue

    PMID:21358633 PMID:22398447 PMID:22855792

    Open questions at the time
    • How BAH domain binding to H4K20me2 is coordinated with other origin-specifying inputs was unclear
    • Whether combined replication and centrosome defects explain the full Meier-Gorlin phenotype was unknown
  8. 2016 High

    Establishing ORC1 as a transcriptional repressor of Cyclin E through RB and SUV39H1: ORC1 was shown to bind RB and SUV39H1 at the CCNE1 promoter to establish H3K9me3 and repress E2F1-dependent transcription, with CDC6 counteracting this repression by recruiting Cyclin E-CDK2 to displace RB — creating a bistable switch for S-phase commitment.

    Evidence Reciprocal Co-IP, ChIP at CCNE1 promoter, siRNA knockdown, reporter assays in human cells

    PMID:27458800

    Open questions at the time
    • Whether ORC1 represses other E2F target genes genome-wide was not tested
    • How ORC1's transcriptional and replication functions are coordinated at the same locus was unclear
  9. 2021 High

    Defining the SLiM-based regulatory logic controlling ORC1 interactions across the cell cycle: IDR-embedded short linear motifs were shown to mediate G1-specific ORC1-CDC6 binding, SKP2-Cyclin A-CDK2-dependent ORC1 destruction in late G1, and PP1 recruitment for ORC1 dephosphorylation at mitotic exit — providing an integrated molecular mechanism for ORC1 oscillation.

    Evidence Domain mapping, mutagenesis, Co-IP, cell-cycle synchronization, ubiquitination and kinase/phosphatase binding assays in human cells

    PMID:33761311

    Open questions at the time
    • Whether PP1-mediated dephosphorylation is the sole mechanism restoring ORC1 chromatin binding was not resolved
    • Structural basis of SLiM-mediated ORC1-CDC6 interaction was unavailable
  10. 2023 High

    Revealing RNA as a regulator of ORC1 chromatin dynamics: ORC1 was found to bind cis-transcribed RNAs via its IDR, with RNA binding promoting ORC1 phosphorylation and chromatin release; disruption of RNA binding impaired proximal origin activation, linking transcription to replication origin firing.

    Evidence CLIP-seq, RNA depletion, ORC1 RNA-binding mutant expression, Repli-seq, phosphorylation and degradation assays

    PMID:37488096

    Open questions at the time
    • Which specific RNA sequences or structures are recognized by ORC1 was not defined
    • Whether RNA-dependent regulation operates at all origins or a specific subset was unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of the full-length human ORC1 in the context of the complete ORC-CDC6-DNA complex, how the multiple IDR-mediated interactions (RNA binding, CDC6 association, PP1 recruitment, phase separation) are spatiotemporally coordinated within a single molecule, and whether the transcriptional repression and centrosome functions of ORC1 are mechanistically integrated with its replication licensing role remain unresolved.
  • No full-length human ORC1 structure exists
  • Mechanistic integration of replication, centrosome, and transcription functions is not established
  • Whether ORC1 phase separation is functionally required in vivo has limited validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0042393 histone binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0005694 chromosome 5 GO:0005634 nucleus 3 GO:0005815 microtubule organizing center 3 GO:0005829 cytosol 2
Pathway
R-HSA-69306 DNA Replication 8 R-HSA-1640170 Cell Cycle 5 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CCNA2CDC6HBO1MCM2ORC2PP1RB1SUV39H1
Complex memberships
ORC (origin recognition complex)pre-replication complex (pre-RC)

Evidence

Reading pass · 34 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 recognition impairs ORC1 occupancy at replication origins, ORC chromatin loading, and cell-cycle progression. Mutations in this BAH domain cause Meier-Gorlin syndrome. Crystal structure of BAH domain bound to H4K20me2 peptide; mutagenesis; ChIP; zebrafish morphant rescue experiments Nature High 22398447
1999 Human ORC1 physically interacts with HBO1 (histone acetyltransferase binding to ORC), a MYST-family HAT that exists in a multisubunit complex with histone H3 and H4 acetyltransferase activity, linking ORC to chromatin acetylation. Co-immunoprecipitation from human cell extracts; biochemical fractionation; HAT activity assay The Journal of biological chemistry High 10438470 11278932
1998 Human CDC6 associates with human ORC1 protein in cells, is nuclear in G1, and is selectively eliminated from the nucleus upon S-phase entry, suggesting ORC1-CDC6 interaction is part of pre-replication complex assembly. Two-hybrid screen; co-immunoprecipitation; cell-cycle-staged immunofluorescence Molecular and cellular biology High 9566895
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 chromatin-bound throughout. Non-chromatin-bound ORC1 is degraded by the 26S proteasome only when released into the cytosol. Chromatin fractionation; ubiquitination assays; proteasome inhibitor (MG132) treatment; cell-cycle synchronization; immunoblotting Molecular and cellular biology High 11739726
2003 Human ORC1 protein levels oscillate during the cell cycle (accumulating in mid-G1, peaking at G1/S, then degrading in S phase) via 26S proteasome-dependent degradation; other ORC subunits (ORC2–5) remain constant. ORC1 knockdown by RNAi causes ORC2 to shift to a nuclease-soluble fraction and blocks MCM loading onto chromatin. Cell-cycle synchronization; immunoblotting with specific antibody; proteasome inhibitor treatment; RNAi; chromatin fractionation The Journal of biological chemistry High 12909626 12909627
2009 ORC1 controls centriole and centrosome copy number in human cells independently of its DNA replication role. Cyclin A promotes ORC1 localization to centrosomes, where ORC1 prevents Cyclin E-dependent reduplication of centrioles and centrosomes within a single cell division cycle. siRNA knockdown; overexpression; centrosome counting; fluorescence microscopy; co-immunoprecipitation with cyclins Science High 19197067
2012 ORC1 harbors a PACT centrosome-targeting domain and a CDK inhibitory domain; the latter differentially inhibits Cyclin E-CDK2 (via a mechanism disrupted by Meier-Gorlin syndrome mutations) and Cyclin A-CDK2 (via a Cy motif). Meier-Gorlin syndrome ORC1 mutations that disrupt Cyclin E-CDK2 inhibition cause centrosome reduplication. Domain mapping; kinase activity assays; site-directed mutagenesis; centrosome reduplication assays; patient mutation analysis Genes & development High 22855792
2004 Cdk1 (Cdc2)/Cyclin A selectively associates with ORC1 during G2/M phase, causing hyperphosphorylation of ORC1 and preventing its binding to chromatin during mitosis; Cdk inhibition in metaphase cells rapidly restores ORC1 chromatin binding. Co-immunoprecipitation; phosphorylation assays; cell-cycle synchronization; Cdk inhibitor treatment; chromatin fractionation Molecular and cellular biology High 15199143
2006 The BAH domain of human ORC1 is required for reassociation of ORC1 with chromosomes during the M-to-G1 transition and for binding to EBV oriP to stimulate oriP-dependent DNA replication; it also promotes ORC2 binding to chromatin upon mitotic exit. The BAH domain is not required for nuclear localization, ORC subunit association, or S-phase degradation of ORC1. BAH domain mutagenesis; oriP-dependent plasmid replication assay; chromatin fractionation; co-immunoprecipitation The EMBO journal High 17066079
2006 Mono-ubiquitylation and hyperphosphorylation of ORC1 during S and G2/M phases respectively cause ORC1 accumulation in the cytoplasm. Without these modifications, ORC1 over-expression induces p53-independent apoptosis; co-expression of ORC2 prevents apoptosis and restores uniform nuclear localization of ORC1. Transient expression of modification mutants; cell fractionation; apoptosis assays; ORC2 co-expression rescue Journal of cell science Medium 16537645
2021 Multiple short linear motifs (SLiMs) within intrinsically disordered regions (IDRs) of ORC1 and CDC6 mediate cell-cycle-dependent protein-protein interactions: an ORC1 IDR domain is required for ORC1-CDC6 interaction in G1 but prevents it in mitosis; a SKP2-Cyclin A-CDK2-dependent mechanism targets ORC1 for destruction in late G1; protein phosphatase 1 binds a SLiM in the ORC1 IDR to cause ORC1 dephosphorylation upon mitotic exit, increasing ORC1 protein levels and promoting pre-RC assembly. Domain mapping; mutagenesis; co-immunoprecipitation; cell-cycle synchronization; ubiquitination assays; kinase/phosphatase binding assays Molecular cell High 33761311
2016 ORC1 represses CCNE1 (Cyclin E gene) transcription by binding to the Retinoblastoma protein (RB), the histone methyltransferase SUV39H1, and its repressive H3K9me3 mark, cooperating with SUV39H1 and RB to repress E2F1-dependent CCNE1 transcription. CDC6 counteracts this by binding Cyclin E-CDK2, which removes RB from ORC1, thereby hyper-activating CCNE1 transcription. Co-immunoprecipitation; chromatin immunoprecipitation; siRNA knockdown; reporter assays eLife High 27458800
2015 ORC1 re-localizes to condensing chromatin during early mitosis via C-terminal sequences similar to mitotic chromosome-binding sequences in FOXA1; it then shows different nuclear localization patterns during G1, remaining associated with late-replicating regions in late G1. ORC1 depletion causes concomitant loss of MCM2-7 helicase proteins from chromatin, indicating ORC1 nucleates ORC assembly and subsequent pre-RC assembly. Time-lapse and live-cell imaging of fluorescently tagged ORC1; domain deletion/mutagenesis; chromatin fractionation; siRNA depletion The Journal of biological chemistry High 25784553
2010 The retinoblastoma protein (Rb) directly binds to ORC1 in vitro and in cells (competitive with E2F1 binding to Rb); Rb and E2F1 associate with replication origins in a cell-cycle-regulated manner, with E2F1 displacement of Rb-bound ORC1 marking G1-to-S transition. GST pull-down; co-immunoprecipitation; chromatin immunoprecipitation at origins across cell cycle PloS one Medium 21085491
2001 MCM2 also interacts with HBO1 directly via an N-terminal domain of MCM2 and the C2HC zinc finger of HBO1; combined with ORC1-HBO1 interaction, this establishes HBO1 as a bridge between two pre-replication complex components. Yeast two-hybrid; in vitro pull-down; co-immunoprecipitation; reverse two-hybrid with suppressor mutant isolation The Journal of biological chemistry High 11278932
2000 ORC1 directly binds c-Myc at its N-terminal region (responsible for gene silencing) in a complex containing other ORC subunits and Max in vivo and in vitro; ORC1 inhibits E-box-dependent transcription by c-Myc through competitive binding to the C-terminal region of c-Myc with SNF5 (a SWI/SNF component). Co-immunoprecipitation; GST pull-down; luciferase reporter assay for E-box-dependent transcription Genes to cells Medium 10886373
2000 Hamster ORC1 is selectively released from chromatin during mitosis and early G1 (while ORC2 remains stably chromatin-bound throughout). ORC1 and MCM3 become stably chromatin-bound during mid-G1, concurrent with the appearance of functional pre-replication complexes at a hamster replication origin. Chromatin fractionation; immunoblotting; functional replication assay; cell-cycle synchronization The EMBO journal High 10835370
2005 Drosophila ORC1 is degraded at end of M phase and throughout G1 by APC activated by Fzr/Cdh1 via a novel destruction motif called the O-box (necessary and sufficient for Fzr/Cdh1-dependent polyubiquitylation in vitro and degradation in vivo), distinct from the D-box or KEN-box. In vitro polyubiquitylation assay; in vivo degradation assay; mutagenesis of O-box; Drosophila genetics Genes & development High 16195415
2001 Viral cyclin/Cdk6 complexes phosphorylate human ORC1 and, like cyclin A overexpression, cause Crm1-dependent nuclear export of ORC1 to the cytoplasm in a manner dependent on phosphorylation of CDK target sites in ORC1. Overexpression of viral cyclin and cyclin A; CRM1 inhibitor (leptomycin B) treatment; immunofluorescence localization; phosphorylation mapping Experimental cell research Medium 11716535
2023 ORC1 binds cis-transcribed RNAs (from genes with origins at their TSSs) via its intrinsically disordered region. RNA binding promotes ORC1 chromatin release by facilitating ORC1 phosphorylation and subsequent degradation; RNA depletion or ORC1 RNA-binding mutants impair proximal origin activation. CLIP-seq; RNA depletion; ORC1 RNA-binding mutant expression; Repli-seq; phosphorylation and degradation assays; phase-separation assays Nature communications High 37488096
2019 Crystal structure of Cyclin A-CDK2 complex bound to an ORC1 peptide at 2.54 Å reveals that the ORC1 KXL motif binds the cyclin binding groove (CBG) of Cyclin A, with an arginine residue flanking the KXL motif inserting into an adjacent acidic pocket to strengthen binding. X-ray crystallography at 2.54 Å; structural analysis; sequence comparison of cyclin binding sites Protein science High 31309634
2019 Structure of yeast Orc1 BAH domain bound to the nucleosome core particle reveals that Orc1 BAH, unlike Sir3 BAH, does not discriminate between acetylated and non-acetylated H4K16; direct nucleosome binding via the BAH domain is essential for Orc1 to maintain rDNA border integrity during meiosis. Cryo-EM/structural study of BAH-nucleosome complex; mutagenesis; meiotic phenotypic analysis Nature communications High 31263106
2010 The conserved N-terminal BAH domain of yeast Orc1 is necessary for stable ORC association with chromosomes and contributes to ORC binding at most yeast origins, with a subset of origins highly dependent on it. This replication function is separable from the BAH domain's role in transcriptional silencing. Genome-wide ORC binding (ChIP-chip); in vivo replication assays; BAH domain deletion/mutagenesis; genetic separation of silencing and replication functions Genes & development High 20595233
2011 ORC1 mutations causing Meier-Gorlin syndrome disrupt known ORC1 functions including pre-replicative complex formation and origin activation; ORC1 deficiency in human cells perturbs S-phase entry and progression; Orc1 depletion in zebrafish markedly reduces body size. Patient mutation analysis; pre-RC formation assays; BrdU incorporation; cell-cycle analysis; zebrafish morpholino knockdown Nature genetics High 21358633
2018 Mouse ORC1 is essential for mitotic cell divisions (global or tissue-specific ablation blocks DNA replication and cell lineage expansion) but is dispensable for endoreduplication in polyploid trophoblast and hepatocyte cells. Conditional knockout mice (LoxP flanking ATPase domain exons); BrdU incorporation; flow cytometry; tissue analysis Genes & development High 29967292
2010 Cyclin A interacts with both MCM5 and ORC1 via its centrosomal localization sequence (CLS) in a Cdk-independent but CLS-dependent manner; this recruits ORC1 and MCM5 to centrosomes to prevent Cyclin E-dependent centrosome reduplication. Co-immunoprecipitation; centrosome localization assays; CLS mutagenesis; hydrophobic patch mutagenesis; centrosome reduplication assay Journal of cell science Medium 20663915
2015 The Meier-Gorlin syndrome mutation R105Q in the ORC1 BAH domain reduces DNA binding affinity to nucleosomal DNA, thereby impairing ORC1BAH-nucleosome interaction and likely influencing DNA replication initiation. Fluorescence polarization binding assays; H4Kc20me2 nucleosome binding assays; mutagenesis ACS chemical biology Medium 25689043
1996 Human ORC1 (HsORC1) expression is regulated by E2F-dependent negative transcription control in quiescent cells; activation of HsORC1 transcription upon growth stimulation requires G1 cyclin-dependent kinase activity, and forced E2F1 expression bypasses this requirement. Promoter analysis; reporter gene assays; E2F1 overexpression; CDK inhibitor treatment; northern blotting Molecular and cellular biology High 8943353
2024 ORC1 is enriched on the HIV-1 LTR promoter and recruits repressive epigenetic elements including DNMT1, HDAC1/2, and histone modifiers (H3K9me3 and H3K27me3) to facilitate HIV-1 latency; ORC1 undergoes liquid-liquid phase separation (LLPS) important for its recruitment to the HIV-1 promoter. CRISPR affinity purification of HIV-1 LTR-associated factors; ChIP; siRNA depletion; latency reactivation assays in cell models and primary CD4+ T cells; LLPS assays Journal of virology Medium 39082875
1999 S. cerevisiae Cdc6 associates with Orc1 in vitro and in vivo; this interaction requires functional ATP-binding of Cdc6 (K114E mutation disrupts both ATP binding and Cdc6-Orc1 association), and loss of Cdc6-Orc1 interaction prevents Mcm5 loading onto chromatin origins. In vitro pull-down; co-immunoprecipitation; site-directed mutagenesis of ATP-binding site; chromatin fractionation; plasmid stability assay The Journal of biological chemistry High 10075735
1996 S. pombe orp1 (ORC1 homolog) is required for an early step of DNA replication at S-phase onset; Orp1p forms protein complexes with Cdc18p and Cdc21p (MCM homolog) in vivo, and orp1 mutants also affect the checkpoint preventing mitosis in the absence of DNA replication. Temperature-sensitive and null mutant analysis; FACS; genetic interaction analysis; co-immunoprecipitation Genes & development High 8895665
2007 Archaeal Cdc6/Orc1 heterodimer structure at 3.4 Å shows that initiators use their AAA+ ATPase domains in addition to conventional DNA-binding elements to recognize origin DNA, inducing substantial DNA strand distortions and establishing polarity of initiator assembly. X-ray crystallography of archaeal Orc1 heterodimer-DNA complex at 3.4 Å; biochemical origin-binding assays Science High 17761879
1999 Sir1p interaction with Orc1p is mediated by a specific 17-amino-acid segment of Sir1p required for silencer recognition; mutations in this segment abolish Sir1p interaction with Orc1p and HMR-E silencer recognition, but silencing function can be restored by tethering Sir1p to a silencer via a heterologous DNA-binding domain. Genetic screen for SIR1 silencing mutations; deletion analysis; two-hybrid interaction assays; tethering rescue experiments in S. cerevisiae Genetics High 9872946
2025 The BAH domain of yeast Orc1 ceases to bind Sir1 in the presence of nucleosomes, suggesting the BAH domain senses chromatin environment to perform dual roles in replication origin specification and transcriptional silencing. Biochemical binding assays; structural analysis of BAH domain-Sir1 and BAH domain-nucleosome interactions bioRxivpreprint Medium bio_10.1101_2025.03.14.643217

Source papers

Stage 0 corpus · 98 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 283 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 170 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 136 8943353
2007 Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex. Science (New York, N.Y.) 128 17761879
2009 Orc1 controls centriole and centrosome copy number in human cells. Science (New York, N.Y.) 120 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
2009 Arabidopsis ORC1 is a PHD-containing H3K4me3 effector that regulates transcription. Proceedings of the National Academy of Sciences of the United States of America 68 19171893
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
2010 The cyclin A centrosomal localization sequence recruits MCM5 and Orc1 to regulate centrosome reduplication. Journal of cell science 54 20663915
2009 Trypanosome prereplication machinery contains a single functional orc1/cdc6 protein, which is typical of archaea. Eukaryotic cell 54 19717742
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
2005 The genes encoding Arabidopsis ORC subunits are E2F targets and the two ORC1 genes are differently expressed in proliferating and endoreplicating cells. Nucleic acids research 45 16179646
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 44 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 40 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 27 34503063
2016 Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. eLife 25 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
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
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 15 17673179
2005 Biochemical characterization of two Cdc6/ORC1-like proteins from the crenarchaeon Sulfolobus solfataricus. Extremophiles : life under extreme conditions 15 16179962
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
2023 Distinct roles of Arabidopsis ORC1 proteins in DNA replication and heterochromatic H3K27me1 deposition. Nature communications 8 36882445
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 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
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 1 40948373
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
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