Affinage

TOPBP1

DNA topoisomerase 2-binding protein 1 · UniProt Q92547

Length
1522 aa
Mass
170.7 kDa
Annotated
2026-06-10
100 papers in source corpus 63 papers cited in narrative 64 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOPBP1 is a multi-BRCT-domain scaffold that couples DNA replication initiation to checkpoint signaling and DNA repair, functioning as the principal activator of the ATR-ATRIP kinase (PMID:16530042, PMID:18922789). Activation is mediated by a dedicated ATR-activating domain (AAD) lying between BRCT repeats VI and VII; a single inactivating substitution in this domain abolishes checkpoint signaling, and the AAD acts on the ATR PIKK regulatory domain through its ATRIP-binding region (PMID:16530042, PMID:18519640). The AAD is intrinsically disordered and drives self-assembly into liquid-liquid phase-separated condensates that amplify ATR/Chk1 output, and contains a coiled-coil motif required for ATR engagement (PMID:33503405, PMID:30940728); in vivo the AAD is essential, as a W1147R knock-in causes embryonic lethality and defective Chk1 signaling (PMID:23950734). TOPBP1 is localized to sites of replication stress and damage through phosphorylation-dependent BRCT interactions: its N-terminal BRCT1-2 reads CK2-phosphorylated Rad9 of the 9-1-1 clamp and the Nbs1 subunit of MRN, BRCT2 binds RPA-coated ssDNA, and additional BRCT surfaces engage 53BP1, MDC1, RHINO/RHNO1 and Treacle to direct it to G1, mitotic, and nucleolar damage (PMID:17575048, PMID:17636252, PMID:23582259, PMID:19279141, PMID:27129245, PMID:31135337, PMID:30898438, PMID:31913317), while tethering TOPBP1 to DNA is itself sufficient to trigger ATR-Chk1 activation (PMID:21502314). Through its C-terminal BRCT7/8, TOPBP1 makes CDK-phosphorylation-dependent contacts with Treslin/Sld3 and the BACH1/FANCJ helicase to load CDC45 and initiate replication and to load RPA, a recognition mode resolved structurally as a phospho-threonine binding cleft (PMID:20116089, PMID:21700459, PMID:20159562, PMID:21127055); this replication-initiation role is conserved from the yeast ortholog Dpb11, which assembles a CDK-dependent pre-loading complex with Sld2, GINS and Pol epsilon (PMID:20231317, PMID:9742127, PMID:16619031, PMID:23629628). TOPBP1 also functions in homologous recombination and genome maintenance, promoting PLK1-mediated RAD51 Ser14 phosphorylation and RAD51 loading and stabilizing BLM helicase against MIB1-mediated degradation (PMID:26811421, PMID:24239288). Akt phosphorylation at Ser1159 induces BRCT7/8-dependent oligomerization that switches TOPBP1 from checkpoint activation to transcriptional repression of E2F1, p53, and mutant p53 (PMID:17006541, PMID:24081328, PMID:19289498). In mitosis, a CK2-phospho-MDC1 interaction recruits TOPBP1 into a CIP2A-MDC1-TOPBP1 complex that forms filaments tethering broken chromosomes (PMID:30898438, PMID:35842428). TOPBP1 abundance is set by a network of stability regulators including PML, Miz1/HectH9, and the OTUD6A-UBR5 ubiquitin axis (PMID:12773567, PMID:18923429, PMID:35768646).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Established that the TOPBP1 ortholog links DNA replication to checkpoint control, defining the core dual function of this protein family before the mammalian gene was characterized.

    Evidence Genetic suppression and synthetic lethality with Pol epsilon subunits in budding yeast dpb11 mutants

    PMID:8524850

    Open questions at the time
    • Did not define the molecular activator role in checkpoint kinase activation
    • No biochemical mechanism of replication initiation
  2. 2001 Medium

    Showed human TOPBP1 is a replication-fork protein that binds Pol epsilon and relocalizes with BRCA1 upon fork stalling, connecting the yeast genetics to a vertebrate replication/damage scaffold.

    Evidence Co-IP, immunofluorescence colocalization, and knockdown in human cells

    PMID:11395493

    Open questions at the time
    • Mechanism of recruitment to stalled forks not resolved
    • No demonstration of direct kinase activation
  3. 2006 High

    Identified the defining biochemical activity: TOPBP1 directly activates ATR-ATRIP via a discrete AAD, answering what TOPBP1 does at the molecular level in the checkpoint.

    Evidence In vitro kinase reconstitution with recombinant proteins, point mutagenesis, Xenopus extract checkpoint assays

    PMID:16530042

    Open questions at the time
    • Did not define how AAD engages ATR structurally
    • Recruitment determinants to chromatin left open
  4. 2007 High

    Defined how TOPBP1 is brought to forks, showing the 9-1-1 clamp recruits TOPBP1 via phospho-Rad9 binding to BRCT1-2, separating localization from intrinsic activation.

    Evidence Co-IP and fusion-protein bypass (AAD-PCNA/H2B) in Xenopus egg extracts, replicated across two papers

    PMID:17575048 PMID:17636252

    Open questions at the time
    • Did not establish whether 9-1-1 is the sole recruiter
    • Phospho-site on Rad9 not yet mapped to a specific kinase
  5. 2008 High

    Mapped the activation interface on the kinase side, defining the ATRIP TopBP1-interacting region and the ATR PRD as essential for TOPBP1-dependent activation.

    Evidence Co-IP, in vitro kinase assays, and site-directed mutagenesis with cellular complementation

    PMID:18519640

    Open questions at the time
    • No atomic structure of the AAD-PRD contact
    • Stoichiometry of activation undefined
  6. 2010 High

    Established the replication-initiation arm in vertebrates, showing CDK-dependent TOPBP1-Treslin binding loads CDC45 at origins, and reconstituted the conserved yeast pre-loading complex.

    Evidence Mass spec, depletion-rescue in Xenopus and human cells, plus in vitro pre-LC reconstitution with purified yeast components

    PMID:20116089 PMID:20231317 PMID:20383140

    Open questions at the time
    • Did not resolve how replication and checkpoint functions are temporally partitioned
    • GEMC1 role mechanistically incomplete
  7. 2010 High

    Defined the kinase generating the recruitment signal, showing CK2 phosphorylates Rad9 to license TOPBP1 binding, and mapped the BACH1 BRCT7/8 phospho-interaction structurally.

    Evidence In vitro CK2 phosphorylation, mutagenesis, UV/MMS sensitivity, and X-ray crystallography of BRCT7/8-phospho-BACH1

    PMID:20159562 PMID:20545769 PMID:21127055

    Open questions at the time
    • Did not connect BACH1 helicase activity to ATR output mechanistically
  8. 2013 High

    Resolved the upstream sensing step, showing MRN recruits TOPBP1 to ssDNA-dsDNA junctions while 9-1-1 licenses its activity, and that ATM-phosphorylated TOPBP1 bridges to MRN via Nbs1.

    Evidence Defined synthetic DNA structures in Xenopus extracts, immunodepletion, and BRCT mutagenesis

    PMID:19279141 PMID:23582259

    Open questions at the time
    • Relative contributions of MRN vs 9-1-1 vs RPA across damage types not unified
    • Order of assembly in human cells incompletely defined
  9. 2013 High

    Demonstrated the AAD is essential in a mammal and that forced TOPBP1 dimerization activates ATR, foreshadowing a higher-order assembly model of activation.

    Evidence W1147R AAD knock-in mouse with embryonic lethality, MEF phenotyping, and enforced dimerization constructs

    PMID:23950734

    Open questions at the time
    • Physiological trigger of oligomerization in vivo not defined
    • Did not establish phase separation
  10. 2013 High

    Revealed a checkpoint-independent transcriptional/oligomerization switch, showing Akt phosphorylation of Ser1159 drives BRCT7/8 oligomerization that suppresses checkpoint recruitment and enables E2F1/p53 repression.

    Evidence Size exclusion chromatography, phosphopeptide binding, mutagenesis, and Chk1 assays

    PMID:17006541 PMID:24081328

    Open questions at the time
    • How the cell chooses between activator and repressor states in vivo unresolved
  11. 2016 Medium

    Extended TOPBP1 into homologous recombination execution, showing BRCT7/8-dependent PLK1 binding promotes RAD51 Ser14 phosphorylation and RAD51 loading.

    Evidence siRNA screen, co-IP, phosphorylation assays, foci, and HR reporter

    PMID:26811421 PMID:27129245

    Open questions at the time
    • Single-lab mechanism for the PLK1-RAD51 axis
    • Direct vs scaffolded phosphorylation not fully separated
  12. 2019 High

    Defined a mitosis-specific role in chromosome tethering, showing CK2-phospho-MDC1 recruits TOPBP1 into filaments that bridge broken chromosomes until repair in the next cell cycle.

    Evidence Phosphoproteomics, super-resolution microscopy, CRISPR cells, and radiosensitivity assays, replicated with CIP2A characterization

    PMID:30898438 PMID:35842428

    Open questions at the time
    • Structural basis of the filament not defined
    • Regulation of filament disassembly in G1 unknown
  13. 2019 High

    Resolved how G1 recruitment is achieved, showing phosphorylated 53BP1 binds TOPBP1 BRCTs in a manner structurally compatible with simultaneous 9-1-1 binding, enabling the G1 checkpoint.

    Evidence X-ray crystallography, mutagenesis, and G1 checkpoint assays, complemented by comprehensive BRCT phospho-ligand specificity mapping

    PMID:30295604 PMID:31135337

    Open questions at the time
    • How combinatorial BRCT occupancy is regulated across cell cycle not defined
  14. 2021 High

    Reframed ATR activation as a condensation-driven switch, showing the disordered AAD undergoes LLPS and that condensation is required for ATR/Chk1 signaling.

    Evidence Optogenetic condensate platform, in vitro LLPS with purified TOPBP1, single-residue mutagenesis, and EM

    PMID:30940728 PMID:33503405

    Open questions at the time
    • In vivo threshold and reversibility of condensation under physiological stress not quantified
  15. 2022 Medium

    Added S-phase HR recruitment and stability control, showing CK2-HTATSF1 directs TOPBP1 to PARylated RPA for RPA-to-RAD51 exchange and that the OTUD6A-UBR5 axis sets TOPBP1 abundance.

    Evidence Co-IP, HR reporter, PARP-inhibitor experiments, ubiquitination assays, and mouse irradiation model

    PMID:35597237 PMID:35768646

    Open questions at the time
    • Integration of multiple parallel recruitment routes into a single quantitative model lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TOPBP1 integrates its many phospho-dependent recruitment inputs and its condensation/oligomerization states into a single decision between replication initiation, checkpoint activation, HR, chromosome tethering, and transcriptional repression remains unresolved.
  • No unified structural model of the active ATR-activating assembly on chromatin
  • Quantitative rules governing the activator-to-repressor switch in vivo are undefined
  • Disease-causing mutations in human TOPBP1 not established in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0003677 DNA binding 2
Localization
GO:0005654 nucleoplasm 3 GO:0005634 nucleus 2 GO:0005730 nucleolus 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-69306 DNA Replication 4 R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
ATRBRIP1CIP2AMDC1NBS1RAD9TP53BP1TRESLIN
Complex memberships
9-1-1 (Rad9-Hus1-Rad1)-TOPBP1 complexATR-ATRIP activation complexCIP2A-MDC1-TOPBP1 complexDpb11-Sld2-GINS-Pol epsilon pre-loading complex

Evidence

Reading pass · 64 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Recombinant TopBP1 directly activates the ATR-ATRIP kinase complex. The ATR-activating domain (AAD) resides in a conserved segment between BRCT repeats VI and VII of TopBP1, distinct from its BRCT repeats. An inactivating point mutation in this domain abolishes checkpoint regulation in Xenopus egg extracts. In vitro kinase assay with recombinant proteins (Xenopus and human ATR), Xenopus egg extract checkpoint assays, point mutagenesis Cell High 16530042
2007 The 9-1-1 clamp (Rad9-Hus1-Rad1) activates ATR-dependent Chk1 signaling by recruiting TopBP1 to stalled replication forks via direct binding of Rad9's C-terminal phosphorylated Ser-373 to the BRCT I-II region of TopBP1. The primary role of the 9-1-1 clamp is thus to localize the ATR activation domain of TopBP1 to the fork. Co-immunoprecipitation in Xenopus egg extracts, pulldown, fusion-protein complementation (AD fused to PCNA/H2B bypasses 9-1-1 requirement), dominant-negative inhibition Genes & development High 17575048 17636252
2008 ATRIP contains a TopBP1-interacting region required for TopBP1-mediated ATR activation; ATR itself contains a PIKK Regulatory Domain (PRD) that is essential for activation by TopBP1 but not for basal kinase activity. Mutations in either the ATRIP TopBP1-binding region or the ATR PRD abolish TopBP1-dependent checkpoint signaling. Co-immunoprecipitation, in vitro kinase assays, site-directed mutagenesis, cellular complementation Genes & development High 18519640
1995 Yeast Dpb11 (TopBP1 ortholog) physically and genetically interacts with DNA polymerase epsilon subunits (Pol2/Dpb2) and is required for S-phase progression and the S-phase checkpoint, as dpb11-1 mutants show defective S-phase and checkpoint failure after HU/MMS treatment. Genetic suppression screen, synthetic lethality, temperature-sensitive mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 8524850
2010 TopBP1 interacts with Treslin (vertebrate Sld3 ortholog) in a Cdk2-dependent manner and together they are required for loading of Cdc45 onto replication origins to initiate DNA replication. Depletion of Treslin from Xenopus egg extracts or human cells strongly inhibits chromosomal DNA replication. Mass spectrometry identification, co-immunoprecipitation, depletion-rescue in Xenopus egg extracts, siRNA in human cells, chromatin fractionation Cell High 20116089
2010 In budding yeast, CDK promotes formation of a pre-loading complex (pre-LC) containing Dpb11, Sld2, DNA polymerase epsilon, and GINS. CDK phosphorylation of Sld2 is required for pre-LC assembly. Reconstituted in vitro with purified components. In vitro reconstitution of the pre-LC with purified Pol epsilon, GINS, Sld2, and Dpb11; phosphorylation assays; genetic interaction analysis Genes & development High 20231317
2001 Human TopBP1 is required for DNA replication, interacts with DNA polymerase epsilon, and in S phase colocalizes with BRCA1 at replication forks; after replication fork stalling, TopBP1 relocalizes to stalled forks together with BRCA1. TopBP1 also interacts with hRad9. Co-immunoprecipitation, immunofluorescence colocalization, siRNA/antisense knockdown The Journal of biological chemistry Medium 11395493
2002 TopBP1 is phosphorylated in response to DNA DSBs in an ATM-dependent manner. TopBP1 forms nuclear foci at DNA damage sites; focus formation requires BRCT5 but not ATM-dependent phosphorylation. Knockdown of TopBP1 reduces cell survival similarly to knockdown of ATR, Chk1, or Hus1. Immunoblot phosphorylation assay, immunofluorescence foci, antisense morpholino knockdown, ATM-deficient cell lines Molecular and cellular biology Medium 11756551
2000 Dpb11 forms a physical complex with DNA polymerase epsilon (Pol epsilon) that associates preferentially with autonomously replicating sequences (ARSs) during S phase. The Dpb11-Pol epsilon association with ARS is required for subsequent recruitment of Pol alpha-primase. In HU-treated dpb11-1 cells, Pol epsilon associates with both early and late origins, while wild-type cells restrict it to early origins, implicating Dpb11 in late-origin firing control. Chromatin immunoprecipitation, co-immunoprecipitation, ARS fragment association assay Molecular and cellular biology High 10733584
1998 Dpb11 physically interacts with Sld2 in a two-hybrid and co-immunoprecipitation assay; high-copy DPB11 and SLD2 reciprocally suppress each other's temperature-sensitive growth. sld2-6 cells show defective DNA replication, indicating Dpb11-Sld2 complex functions at replication initiation. Yeast two-hybrid, co-immunoprecipitation, synthetic lethality, dosage suppression, replication intermediate analysis Molecular and cellular biology High 9742127
2006 CDK-dependent phosphorylation of Sld2 at Thr84 (via a hierarchical mechanism where canonical CDK sites regulate accessibility of Thr84) is required for Sld2-Dpb11 complex formation and is essential for DNA replication. Phosphorylation of canonical CDK motifs in Sld2 does not directly mediate Dpb11 binding but renders Thr84 accessible. In vitro phosphorylation, site-directed mutagenesis, co-immunoprecipitation, cell viability assays The EMBO journal High 16619031
2008 Yeast Dpb11 directly activates Mec1-Ddc2 (ATR-ATRIP ortholog) kinase activity in vitro for phosphorylation of Rad53 and RPA, independently of DNA. Dpb11 and the 9-1-1 clamp independently activate Mec1, with synergistic activation when both are present. In vitro kinase assay with purified recombinant proteins The Journal of biological chemistry High 18922789
2008 Dpb11 physically and genetically interacts with Mec1-Ddc2; the C-terminal domain of Dpb11 is sufficient to associate with and strongly stimulate Mec1 kinase in a Ddc2-dependent manner. Mec1 phosphorylates Dpb11, which amplifies Dpb11's stimulating effect on Mec1 kinase activity (positive feedback). Co-immunoprecipitation, in vitro kinase assay, genetic complementation Proceedings of the National Academy of Sciences of the United States of America High 19028869
2006 TopBP1 interacts specifically with E2F1 (but not E2F2, E2F3, or E2F4) via BRCT6 of TopBP1 and the N-terminus of E2F1 in a damage-inducible, ATM-dependent manner. TopBP1 represses E2F1 transcriptional activity, S-phase induction, and apoptosis, and recruits E2F1 to BRCA1-containing foci. Co-immunoprecipitation, reporter assay, immunofluorescence Molecular and cellular biology Medium 12697828
2004 TopBP1 represses E2F1-dependent apoptosis through a pRb-independent but Brg1/Brm-dependent mechanism: TopBP1 recruits the SWI/SNF chromatin-remodeling component Brg1/Brm to E2F1-responsive promoters and represses E2F1 (but not E2F2/E2F3) activity. TopBP1 is itself induced by E2F and interacts with E2F1 during G1/S, forming a negative feedback loop. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assay, RNA interference Genes & development Medium 15075294
2013 The MRN complex (MRE11-RAD50-NBS1) is required for recruitment of TOPBP1 to ATR-activating DNA structures (ssDNA-dsDNA junctions) in Xenopus egg extracts. MRN recruits TOPBP1 while the 9-1-1 complex is not required for TOPBP1 recruitment but is required for TOPBP1 function (activation of ATR). Xenopus egg extract with defined synthetic DNA structures, immunodepletion, chromatin fractionation, Chk1 phosphorylation assay Molecular cell High 23582259
2009 The Mre11-Rad50-Nbs1 (MRN) complex bridges ATM and TopBP1 in Xenopus egg extracts. ATM associates with and phosphorylates TopBP1 on S1131, enhancing its ability to activate ATR-ATRIP. TopBP1 associates with MRN via the Nbs1 subunit, mediated by BRCT I-II of TopBP1 and the tandem BRCT repeats of Nbs1. Co-immunoprecipitation in Xenopus egg extracts, immunodepletion, in vitro phosphorylation assay, BRCT domain mutagenesis Molecular biology of the cell High 19279141
2006 TopBP1 depletion by RNAi strongly impairs phosphorylation of multiple ATR targets (Chk1, Nbs1, Smc1, H2AX) but does not prevent ATR assembly at DNA damage sites, demonstrating TopBP1 is required for ATR kinase activation but not for ATR recruitment. TopBP1 is required for damage-induced interaction between Claspin and Chk1, placing TopBP1 upstream of Claspin in the ATR-Chk1 signaling pathway. RNAi knockdown, immunofluorescence colocalization, co-immunoprecipitation, phosphorylation assays Molecular and cellular biology Medium 16880517
2010 TopBP1 is required for recruitment of both 9-1-1 and DNA polymerase alpha (pol alpha) to stalled replication forks in Xenopus egg extracts. Pol alpha is directly required for Rad9 loading, identifying an assembly pathway in which TopBP1 controls 9-1-1 loading at stalled forks via pol alpha. Xenopus egg extract depletion experiments, chromatin fractionation, immunoblotting The Journal of cell biology Medium 19289795
2006 Akt/PKB phosphorylates TopBP1 in vitro and in vivo, inducing oligomerization of TopBP1 through its 7th and 8th BRCT domains. This oligomerization is required for TopBP1 to bind and repress E2F1 and to interact with Miz1 and HPV16 E2. In vitro kinase assay, co-immunoprecipitation, size exclusion chromatography, mutagenesis The EMBO journal Medium 17006541
2013 Akt-phosphorylated TopBP1 at Ser-1159 undergoes oligomerization via intramolecular binding of pS1159 to its own BRCT7/8 domains. This oligomerization represses TopBP1's checkpoint-activating function by preventing its recruitment to chromatin and ATR binding under replicative stress. Thus Akt switches TopBP1 from checkpoint activator to transcriptional regulator. In vitro size exclusion chromatography, phosphopeptide binding assay, mutagenesis, Chk1 phosphorylation assay Molecular and cellular biology High 24081328
2011 In budding yeast, Dpb11 forms a ternary complex with Mec1 and Rad9 required for efficient Rad9 phosphorylation by Mec1. CDK phosphorylation of Rad9 on two key residues generates a binding site for tandem BRCT repeats of Dpb11, recruiting Rad9 into the complex. This mechanism restricts checkpoint signaling to phases when CDK is active (not G1). In vitro kinase assay reconstitution of ternary complex, mutagenesis, co-immunoprecipitation, in vivo checkpoint assays The EMBO journal High 21946560
2010 GEMC1 (a novel vertebrate protein) binds TopBP1, which promotes GEMC1 loading onto chromatin during pre-RC formation. TopBP1-GEMC1-Cdk2/CyclinE interaction is required for Cdc45 loading at replication origins. GEMC1 depletion prevents DNA replication in Xenopus extracts and vertebrate cells. Co-immunoprecipitation, Xenopus egg extract depletion, morpholino/siRNA knockdown, chromatin fractionation Nature cell biology Medium 20383140
2011 The CDK-phosphorylation-dependent interaction between Treslin/ticrr (human Sld3 ortholog) and TopBP1 is conserved in humans. Two CDK phosphorylation sites in Treslin are essential for DNA replication and mediate interaction with the orthologous pair of BRCT repeats in TopBP1. DNA replication stress prevents this interaction via the Chk1 checkpoint kinase. Mutagenesis, co-immunoprecipitation, DNA replication assays, sequence analysis Current biology : CB High 21700459
2011 MDC1 interacts with TopBP1 via the fifth BRCT domain of TopBP1 and the SDT repeats of MDC1. The H2AX/MDC1 signaling cascade promotes TopBP1 accumulation at stalled replication forks and MDC1 is important for ATR-dependent Chk1 activation under replication stress. Co-immunoprecipitation, siRNA knockdown, chromatin fractionation, Chk1 phosphorylation assay The Journal of cell biology Medium 21482717
2019 MDC1 contains a CK2-phosphorylated protein-interaction surface recognized by TOPBP1. This MDC1-TOPBP1 interaction is required specifically for TOPBP1 recruitment to DSBs in mitotic (but not interphase) cells. TOPBP1 forms filamentous structures that bridge MDC1 foci at DSBs in mitosis, functioning to tether broken chromosomes until repair in the next G1 phase. Phosphoproteomics, co-immunoprecipitation, mutagenesis, super-resolution microscopy, CRISPR cell line generation, radiosensitivity assays Molecular cell High 30898438
2022 CIP2A forms a mitosis-specific complex with TOPBP1 and MDC1 at DNA DSBs. CIP2A is cytoplasmic in interphase but enters the nucleus upon nuclear envelope breakdown and promotes TOPBP1 recruitment to mitotic DSBs. Loss of CIP2A causes micronuclei, chromosomal instability, and radiosensitivity. Co-immunoprecipitation, CRISPR knockout, immunofluorescence, subcellular fractionation, chromosome instability assays Nature communications High 35842428
2021 TopBP1 self-assembles into micrometer-sized condensates via its intrinsically disordered ATR activation domain (AAD). Single amino acid substitutions in the AAD disrupt condensation and abolish ATR/Chk1 signaling. Purified TopBP1 undergoes liquid-liquid phase separation in vitro, and condensate formation is a molecular switch amplifying ATR activity. Optogenetic condensate platform, in vitro LLPS with purified TopBP1, single amino acid mutagenesis, ATR/Chk1 kinase assays, electron microscopy of condensate ultrastructure Molecular cell High 33503405
2011 RHINO independently binds both the 9-1-1 complex and TopBP1, is recruited to DNA damage sites by the 9-1-1 complex, and is required for full ATR-mediated Chk1 activation. siRNA screen for checkpoint loss, co-immunoprecipitation, immunofluorescence recruitment assay, Chk1 phosphorylation assay Science (New York, N.Y.) Medium 21659603
2010 BACH1/FANCJ helicase specifically interacts with the C-terminal tandem BRCT7/8 domains of TopBP1, mediated by phosphorylation of BACH1 at Thr1133 in S phase. Both TopBP1 and BACH1 are required for RPA loading onto chromatin and ATR-dependent phosphorylation events after replication stress. Co-immunoprecipitation, domain mapping, phosphorylation assays, chromatin fractionation, siRNA Molecular cell Medium 20159562
2010 Crystal structure of TopBP1 BRCT7/8 domains bound to a BACH1 phospho-Thr1133 peptide reveals a dramatic conformational change in which the two BRCT repeats pivot about the central interface to create a deep peptide-binding cleft. This is the first structural mechanism for Thr(P) recognition by BRCT domains. X-ray crystallography, mutagenesis, phosphopeptide binding assays The Journal of biological chemistry High 21127055
2016 TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation; TOPBP1 physically binds PLK1 and promotes PLK1-mediated phosphorylation of RAD51 at Ser14, a modification required for RAD51 recruitment to chromatin and homologous recombination. siRNA screen, co-immunoprecipitation, phosphorylation assays, immunofluorescence foci, HR reporter assay The Journal of cell biology Medium 26811421
2008 Miz1 recruits a fraction of TopBP1 to chromatin and protects it from proteasomal degradation mediated by the HectH9 ubiquitin ligase. Myc antagonizes TopBP1-Miz1 binding, causing TopBP1 to dissociate from chromatin and be degraded, thereby attenuating ATR signaling. Co-immunoprecipitation, ubiquitination assay, chromatin fractionation, ATR signaling readout, siRNA The EMBO journal Medium 18923429
2013 TopBP1 interacts with BLM helicase in a phosphorylation (BLM Ser304) and cell-cycle-dependent manner; TopBP1 stabilizes BLM by protecting it from MIB1 E3-ligase-mediated ubiquitination and degradation specifically in S phase. TopBP1 depletion causes increased sister chromatid exchanges. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, siRNA Molecular cell Medium 24239288
2015 The BLM-TopBP1 interaction requires BLM phosphorylation on Ser304 (not Ser338 as previously proposed). Disrupting BLM-TopBP1 binding does not affect BLM stability but causes increased sister chromatid exchanges, elevated replication origin firing, and chromosomal aberrations. Co-immunoprecipitation with phosphomutants, BLM stability assays, SCE assay, DNA fiber assay, CRISPR mutant cells Molecular cell Medium 25794620
2011 TopBP1 interacts with 53BP1 via BRCT domains 4-5 of TopBP1, and this interaction mediates TopBP1 recruitment to sites of DNA DSBs specifically in G1. TopBP1 depletion causes G1 checkpoint defect, demonstrating TopBP1 contributes to the G1 DNA damage checkpoint via 53BP1. Co-immunoprecipitation, immunofluorescence, BRCT domain mutagenesis, siRNA, S-phase entry assay The EMBO journal Medium 20871591
2019 Phosphorylation of conserved N-terminal sites in 53BP1 generates a binding site for BRCT domains of TOPBP1. Mutation of these sites abolishes TOPBP1, ATR, and CHK1 recruitment to 53BP1 damage foci, abrogating G1 checkpoint arrest. TOPBP1 interaction with 53BP1 is structurally complementary to its interaction with RAD9-RAD1-HUS1, allowing simultaneous binding. X-ray crystallography, mutagenesis, co-immunoprecipitation, immunofluorescence, G1 checkpoint assay eLife High 31135337
2018 Structural and biochemical characterization of TOPBP1 BRCT domains with diverse phospho-ligands (RAD9, Treslin, RHNO1, MDC1/Mdb1) defines determinants of BRCT domain specificity within the conserved N-terminal region of TOPBP1/Rad4, and identifies previously unknown phosphorylation-dependent binding motifs in RHNO1. X-ray crystallography, phosphopeptide binding assays, mutagenesis eLife High 30295604
2013 The inter-BRCT region of Dpb11/TopBP1 (between BRCT1-2 and BRCT3-4 pairs) directly interacts with GINS, and this interaction is required for efficient initiation of DNA replication in both budding yeast and vertebrate cells. Co-immunoprecipitation, mutagenesis, yeast growth and replication assays Molecular and cellular biology Medium 23629628
2010 Mec1 mediates a key phosphorylation-dependent interaction between the fork protein Dpb11 and the DNA repair scaffolds Slx4-Rtt107. Slx4 and Rtt107 jointly bind Dpb11 and Slx4 phosphorylation (at Mec1 sites) is required. Disruption impairs cellular response to alkylation-induced replication fork blockage. Co-immunoprecipitation, phosphorylation site mutagenesis, MMS sensitivity assay Molecular cell Medium 20670896
2015 TOPBP1 interacts with TOP2A (topoisomerase IIα) via its C-terminal region and is required for TOP2A recruitment to ultra-fine anaphase bridges (UFBs) in mitosis. TOPBP1 recruitment to UFBs requires BRCT domain 5. Depletion of TOPBP1 causes accumulation of UFBs primarily from centromeric loci. Co-immunoprecipitation, domain mapping, immunofluorescence, siRNA depletion, UFB quantification Nature communications Medium 25762097
2015 TopBP1 forms foci upon mitotic entry, marks and promotes unscheduled DNA synthesis at these sites, and is required for focus formation of SLX4 in mitosis. Temporal depletion of TopBP1 before mitosis induces 53BP1 nuclear body formation in daughter G1 cells, demonstrating TopBP1 acts to reduce transmission of DNA damage. Auxin-inducible degron for temporal TopBP1 depletion, immunofluorescence, BrdU incorporation for DNA synthesis The Journal of cell biology Medium 26283799
2003 TopBP1 interacts with E2F1 via BRCT6; this interaction is specific to E2F1 and depends on ATM-dependent phosphorylation of E2F1 after DNA damage. The interaction represses E2F1 transcriptional activity and relocates E2F1 to BRCA1-containing foci. Co-immunoprecipitation, reporter assays, immunofluorescence, domain deletion analysis Molecular and cellular biology Medium 12697828
2009 TopBP1 represses p53 via interaction between BRCT7/8 of TopBP1 and the DNA-binding domain of p53, inhibiting p53 promoter binding activity. TopBP1 overexpression (at levels found in breast cancers) inhibits p53 target gene expression and DNA damage-induced apoptosis/G1 arrest. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assay, siRNA, luciferase/mRNA expression analysis Molecular and cellular biology Medium 19289498
2011 TopBP1 mediates mutant p53 gain-of-function by interacting with p53 hotspot mutants and NF-YA, promoting mutant p53 and p300 recruitment to NF-Y target gene promoters, and by facilitating mutant p53 inhibition of p63/p73 transcriptional activities. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, siRNA, xenograft model Molecular and cellular biology Medium 21930790
2003 PML coimmunoprecipitates with TopBP1 and colocalizes at IR-induced foci; PML is required for TopBP1 nuclear focus formation after IR, and PML overexpression stabilizes TopBP1 protein (pulse-chase analysis) without increasing TopBP1 mRNA, identifying PML as a regulator of TopBP1 protein stability. Co-immunoprecipitation, immunofluorescence, siRNA, adenoviral overexpression, pulse-chase protein stability assay Molecular and cellular biology Medium 12773567
2014 SIRT1 deacetylates TopBP1 and the deacetylated form of TopBP1 represses replication origin firing; loss of SIRT1 results in increased origin firing and defective intra-S-phase checkpoint linked to increased TopBP1 acetylation. SIRT1 thus acts upstream of TopBP1 in controlling origin firing. Proteomics, co-immunoprecipitation, deacetylation assay, DNA fiber assay, siRNA Molecular cell Medium 25454945
2016 TopBP1 makes a direct interaction via its BRCT2 domain with RPA-coated single-stranded DNA. A point mutant abolishing this interaction fails to accumulate at DNA damage sites and cannot activate ATR, identifying this as the mechanism for TopBP1 recruitment to stalled forks. Protein-DNA binding assays, Xenopus egg extract functional studies, mutagenesis, chromatin fractionation, ATR activation assay The Journal of biological chemistry Medium 27129245
2010 Casein kinase 2 (CK2) phosphorylates human Rad9 at Ser341 and Ser387, and this phosphorylation (particularly Ser387) is required for interaction with TopBP1. In vitro CK2-phosphorylated 9-1-1 binds TopBP1, and cells expressing phospho-deficient Rad9 (S341A/S387A) are hypersensitive to UV and MMS. In vitro kinase assay, co-immunoprecipitation, mutagenesis, UV/MMS sensitivity assay Genes to cells : devoted to molecular & cellular mechanisms Medium 20545769
2011 Directly tethering TopBP1 to DNA (via lac repressor/operator) is sufficient to induce ATR phosphorylation of Chk1 both in vitro and in mammalian cells; co-tethering of Claspin with TopBP1 synergistically activates ATR-Chk1 signaling. Lac repressor tethering system in vitro and in vivo, Chk1 phosphorylation assay The Journal of biological chemistry Medium 21502314
2019 Both TopBP1 and ETAA1 ATR activation domains (AADs) contain a predicted coiled-coil motif required for ATR activation. Mutation of the coiled coil impairs AAD-ATR binding without affecting AAD oligomerization. The coiled-coil motif defines a shared structural feature for ATR activation by both activators. In vitro ATR kinase assay, co-immunoprecipitation, immunofluorescence signaling readout, bioinformatic analysis, mutagenesis The Journal of biological chemistry Medium 30940728
2020 In the nucleolus, TOPBP1 recruitment following rDNA DSBs is mediated by ATM- and NBS1-dependent phosphorylation of Treacle (nucleolar phosphoprotein); phosphorylated C-terminal Treacle residues bind three BRCT domains of TOPBP1. TOPBP1 recruitment is required for ATR activation, inhibition of rRNA synthesis, and nucleolar segregation after rDNA damage. Co-immunoprecipitation, phosphomutant analysis, immunofluorescence, ATR/rRNA assays, siRNA Nature communications Medium 31913317
2022 CK2 phosphorylates HTATSF1 to facilitate its binding to TOPBP1; HTATSF1 recognizes poly(ADP-ribosyl)ated RPA at DSBs and recruits TOPBP1 to damaged chromatin in S phase, promoting RPA-to-RAD51 exchange and homologous recombination. Co-immunoprecipitation, phosphorylation assays, HR reporter, RPA/RAD51 foci assays, PARP inhibitor experiments Molecular cell Medium 35597237
2014 Dpb11 (yeast TopBP1) plays opposing roles in DNA end resection by coordinating Rad9 stabilization and exclusion at DSBs. Mec1 kinase promotes the pro-resection function of Dpb11 via Slx4 scaffold interaction. Human TOPBP1 similarly engages 53BP1 (anti-resection) and BRCA1 (pro-resection), suggesting a conserved role in HR control. Co-immunoprecipitation, phosphomutant epistasis, HR assay, SCE quantification, immunofluorescence The Journal of cell biology Medium 28228534
2013 TopBP1/Dpb11 binds UFBs (ultra-fine DNA bridges) together with RPA during anaphase in both yeast (S. cerevisiae) and chicken (DT40) cells. Depletion of TopBP1/Dpb11 leads to accumulation of chromatin bridges, indicating an evolutionarily conserved role in resolving anaphase bridges. Immunofluorescence, conditional depletion in yeast and DT40 cells, bridge quantification The Journal of cell biology Medium 24379413
2017 TOPBP1 is essential for meiotic sex chromosome inactivation (MSCI) in male mice; conditional deletion during pachynema causes germ cell elimination with defective X chromosome gene silencing. TOPBP1 is required for localization of BRCA1, ATR, γH2AFX, and repressive histone marks to the X chromosome, acting via its ATR activation domain. Conditional knockout mouse, immunofluorescence, γH2AFX ChIP, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 29114052
2017 Budding yeast Fun30 (chromatin remodeler) interacts with Dpb11 and this interaction is cell cycle regulated. Human SMARCAD1 (Fun30 ortholog) similarly interacts with TOPBP1. This Dpb11-Fun30 assembly with the 9-1-1 complex localizes Fun30 to DSBs and is required for efficient long-range resection. Artificial targeting of Fun30 to DSBs bypasses cell cycle regulation of resection. Co-immunoprecipitation, cell-cycle phosphomutants, DSB resection assay, DNA fiber analysis, artificial tethering eLife Medium 28063255
2019 GSK-3 kinases regulate TopBP1 protein stability; inhibition or knockdown of GSK-3 causes TopBP1 degradation, limiting ATR activation and Chk1 phosphorylation in response to replication stress. GSK-3 inhibitor treatment, siRNA, immunoblot for TopBP1 and ATR pathway readouts Clinical cancer research Low 31533931
2022 The deubiquitinase OTUD6A interacts with TopBP1, blocks TopBP1 interaction with its E3 ubiquitin ligase UBR5, and thereby reduces K48-linked polyubiquitination of TopBP1 and increases TopBP1 stability following DNA damage. PP2A dephosphorylates OTUD6A at S70/71/74 to promote its nuclear localization after damage. Co-immunoprecipitation, ubiquitination assay, immunofluorescence, siRNA/knockout, mouse irradiation model Cell death and differentiation Medium 35768646
2013 TopBP1 physically interacts with BLM helicase (phospho-Ser304 dependent) to protect BLM from MIB1 E3 ligase-mediated ubiquitination and degradation in S phase; TopBP1 depletion leads to decreased BLM levels and increased SCE. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, siRNA Molecular cell Medium 24239288
2004 TopBP1 localizes to centrosomes in late mitosis in a manner similar to other DNA damage response proteins (BRCA1, p53), and is associated with chromosome cores/axes and the X-Y pair during meiotic prophase I in testis. Immunofluorescence microscopy, immunohistochemistry on testis sections Chromosoma Low 15138768
2014 A cell cycle-regulated Dpb11-Slx4 complex controls JM (joint molecule) resolution by Mus81-Mms4 endonuclease: CDK1-mediated phosphorylation of Slx4 promotes Dpb11-Slx4 interaction; in mitosis, Polo-like kinase Cdc5 phosphorylation of Mms4 promotes Mus81-Mms4 association with the Dpb11-Slx4 complex; the DNA damage checkpoint counteracts this last step. Co-immunoprecipitation, phosphomutant analysis, in vivo JM resolution assay, two-dimensional gel electrophoresis Genes & development Medium 25030699
2013 TopBP1 AAD (W1147R knock-in mutation) is required for ATR activation in vivo: TopBP1-W1147R mice show early embryonic lethality and MEFs with this mutation display impaired cell proliferation, premature senescence, and compromised Chk1 signaling after UV. Enforced TopBP1 dimerization promotes ATR-dependent Chk1 phosphorylation. Knock-in mouse model, MEF analysis, Chk1 signaling assay, enforced dimerization construct PLoS genetics High 23950734
2009 TopBP1, together with damaged DNA containing BPDE adducts, cooperatively stimulates ATR kinase activity on Chk1 and p53. The C-terminus of TopBP1 binds preferentially to damaged (not undamaged) DNA and mediates damaged DNA-dependent ATR activation; TopBP1 binding to DNA is end-independent and shows preference for longer DNA fragments. In vitro kinase assay with purified proteins, DNA-binding assays with damaged/undamaged DNA, gel retardation Nucleic acids research Medium 19139065

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 TopBP1 activates the ATR-ATRIP complex. Cell 620 16530042
2007 The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1. Genes & development 388 17575048
2008 TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes & development 296 18519640
1995 Dpb11, which interacts with DNA polymerase II(epsilon) in Saccharomyces cerevisiae, has a dual role in S-phase progression and at a cell cycle checkpoint. Proceedings of the National Academy of Sciences of the United States of America 236 8524850
2007 The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. The Journal of biological chemistry 232 17636252
2010 Treslin collaborates with TopBP1 in triggering the initiation of DNA replication. Cell 208 20116089
2010 CDK-dependent complex formation between replication proteins Dpb11, Sld2, Pol (epsilon}, and GINS in budding yeast. Genes & development 201 20231317
2011 A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science (New York, N.Y.) 184 21659603
2001 BRCT domain-containing protein TopBP1 functions in DNA replication and damage response. The Journal of biological chemistry 175 11395493
2002 A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival. Molecular and cellular biology 151 11756551
2000 Dpb11 controls the association between DNA polymerases alpha and epsilon and the autonomously replicating sequence region of budding yeast. Molecular and cellular biology 144 10733584
2006 Claspin operates downstream of TopBP1 to direct ATR signaling towards Chk1 activation. Molecular and cellular biology 142 16880517
2005 Identification and functional analysis of TopBP1 and its homologs. DNA repair 142 15897014
1998 Sld2, which interacts with Dpb11 in Saccharomyces cerevisiae, is required for chromosomal DNA replication. Molecular and cellular biology 134 9742127
2010 BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Molecular cell 132 20159562
2004 TopBP1 recruits Brg1/Brm to repress E2F1-induced apoptosis, a novel pRb-independent and E2F1-specific control for cell survival. Genes & development 127 15075294
2013 A role for the MRN complex in ATR activation via TOPBP1 recruitment. Molecular cell 125 23582259
2003 Regulation of E2F1 by BRCT domain-containing protein TopBP1. Molecular and cellular biology 122 12697828
2011 Regulation of DNA replication through Sld3-Dpb11 interaction is conserved from yeast to humans. Current biology : CB 115 21700459
2008 Phosphorylation of the budding yeast 9-1-1 complex is required for Dpb11 function in the full activation of the UV-induced DNA damage checkpoint. Molecular and cellular biology 107 18541674
2011 Dpb11 coordinates Mec1 kinase activation with cell cycle-regulated Rad9 recruitment. The EMBO journal 106 21946560
2011 TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73. Molecular and cellular biology 104 21930790
2019 MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during Mitosis. Molecular cell 103 30898438
2008 Yeast DNA replication protein Dpb11 activates the Mec1/ATR checkpoint kinase. The Journal of biological chemistry 103 18922789
2014 TopBP1: A BRCT-scaffold protein functioning in multiple cellular pathways. DNA repair 101 25087188
2008 Dpb11 activates the Mec1-Ddc2 complex. Proceedings of the National Academy of Sciences of the United States of America 101 19028869
1999 DRC1, DNA replication and checkpoint protein 1, functions with DPB11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 101 10097122
2021 The CIP2A-TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer. Nature cancer 93 35121901
2021 TopBP1 assembles nuclear condensates to switch on ATR signaling. Molecular cell 92 33503405
2010 GEMC1 is a TopBP1-interacting protein required for chromosomal DNA replication. Nature cell biology 92 20383140
2002 A Functional interaction between the human papillomavirus 16 transcription/replication factor E2 and the DNA damage response protein TopBP1. The Journal of biological chemistry 91 11934899
2009 TopBP1 and DNA polymerase-alpha directly recruit the 9-1-1 complex to stalled DNA replication forks. The Journal of cell biology 89 19289795
2006 Regulation of TopBP1 oligomerization by Akt/PKB for cell survival. The EMBO journal 88 17006541
2013 TopBP1/Dpb11 binds DNA anaphase bridges to prevent genome instability. The Journal of cell biology 87 24379413
2011 MDC1 collaborates with TopBP1 in DNA replication checkpoint control. The Journal of cell biology 85 21482717
2003 PML colocalizes with and stabilizes the DNA damage response protein TopBP1. Molecular and cellular biology 85 12773567
2015 TopBP1 is required at mitosis to reduce transmission of DNA damage to G1 daughter cells. The Journal of cell biology 84 26283799
2010 DNA damage signaling recruits the Rtt107-Slx4 scaffolds via Dpb11 to mediate replication stress response. Molecular cell 83 20670896
2006 A CDK-catalysed regulatory phosphorylation for formation of the DNA replication complex Sld2-Dpb11. The EMBO journal 83 16619031
2014 A cell cycle-regulated Slx4-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication. Genes & development 82 25030699
2009 A tale of two tails: activation of DNA damage checkpoint kinase Mec1/ATR by the 9-1-1 clamp and by Dpb11/TopBP1. DNA repair 80 19464966
2010 TopBP1 functions with 53BP1 in the G1 DNA damage checkpoint. The EMBO journal 77 20871591
2015 STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication. mBio 76 26695634
1999 Conserved BRCT regions of TopBP1 and of the tumor suppressor BRCA1 bind strand breaks and termini of DNA. Oncogene 76 10498869
2016 TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. The Journal of cell biology 71 26811421
2008 Miz1 and HectH9 regulate the stability of the checkpoint protein, TopBP1. The EMBO journal 71 18923429
2004 TopBP1 and ATR colocalization at meiotic chromosomes: role of TopBP1/Cut5 in the meiotic recombination checkpoint. Molecular biology of the cell 71 14718568
2015 TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution. Nature communications 70 25762097
2002 Genetic and physical interactions between DPB11 and DDC1 in the yeast DNA damage response pathway. Genetics 69 11973288
2014 Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension. American journal of respiratory and critical care medicine 66 24702692
2015 Evidence supporting a role for TopBP1 and Brd4 in the initiation but not continuation of human papillomavirus 16 E1/E2-mediated DNA replication. Journal of virology 65 25694599
2020 Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation. Nature communications 64 31913317
2019 Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to Chemotherapy by Abrogating the TopBP1/ATR-Mediated DNA Damage Response. Clinical cancer research : an official journal of the American Association for Cancer Research 64 31533931
2009 The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM. Molecular biology of the cell 61 19279141
2015 TopBP1 interacts with BLM to maintain genome stability but is dispensable for preventing BLM degradation. Molecular cell 59 25794620
2010 TopBP1 deficiency causes an early embryonic lethality and induces cellular senescence in primary cells. The Journal of biological chemistry 59 21149450
2005 Human TopBP1 ensures genome integrity during normal S phase. Molecular and cellular biology 59 16314514
2009 Regulation of p53 by TopBP1: a potential mechanism for p53 inactivation in cancer. Molecular and cellular biology 58 19289498
2013 An essential function for the ATR-activation-domain (AAD) of TopBP1 in mouse development and cellular senescence. PLoS genetics 56 23950734
2012 Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors. Nature neuroscience 54 22522401
2009 TopBP1 and DNA polymerase alpha-mediated recruitment of the 9-1-1 complex to stalled replication forks: implications for a replication restart-based mechanism for ATR checkpoint activation. Cell cycle (Georgetown, Tex.) 54 19652550
2022 The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis. Nature communications 50 35842428
2013 TopBP1 controls BLM protein level to maintain genome stability. Molecular cell 49 24239288
2019 Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint. eLife 48 31135337
2017 Targeting of the Fun30 nucleosome remodeller by the Dpb11 scaffold facilitates cell cycle-regulated DNA end resection. eLife 48 28063255
2014 A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint. Molecular cell 48 25454945
2012 An interaction between human papillomavirus 16 E2 and TopBP1 is required for optimum viral DNA replication and episomal genome establishment. Journal of virology 48 22973044
2010 Molecular basis of BACH1/FANCJ recognition by TopBP1 in DNA replication checkpoint control. The Journal of biological chemistry 48 21127055
2004 Expression of MCM10 and TopBP1 is regulated by cell proliferation and UV irradiation via the E2F transcription factor. Oncogene 45 15195143
1999 CDC45 and DPB11 are required for processive DNA replication and resistance to DNA topoisomerase I-mediated DNA damage. Proceedings of the National Academy of Sciences of the United States of America 45 10500195
2017 TOPBP1Dpb11 plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1Rad9. The Journal of cell biology 44 28228534
2014 Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy. Nature communications 44 25400145
2009 Cooperative activation of the ATR checkpoint kinase by TopBP1 and damaged DNA. Nucleic acids research 44 19139065
2022 Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy. Cell death and differentiation 43 35768646
2012 S-phase sensing of DNA-protein crosslinks triggers TopBP1-independent ATR activation and p53-mediated cell death by formaldehyde. Cell cycle (Georgetown, Tex.) 43 22722496
2014 TopBP1 and Claspin contribute to the radioresistance of lung cancer brain metastases. Molecular cancer 42 25216549
2013 Efficient initiation of DNA replication in eukaryotes requires Dpb11/TopBP1-GINS interaction. Molecular and cellular biology 41 23629628
2021 CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis. Cancer research 39 34145035
2016 Direct Binding to Replication Protein A (RPA)-coated Single-stranded DNA Allows Recruitment of the ATR Activator TopBP1 to Sites of DNA Damage. The Journal of biological chemistry 39 27129245
2014 SIRT1 deacetylates TopBP1 and modulates intra-S-phase checkpoint and DNA replication origin firing. International journal of biological sciences 39 25516717
2010 Casein kinase 2-dependent phosphorylation of human Rad9 mediates the interaction between human Rad9-Hus1-Rad1 complex and TopBP1. Genes to cells : devoted to molecular & cellular mechanisms 38 20545769
2017 DNA damage response protein TOPBP1 regulates X chromosome silencing in the mammalian germ line. Proceedings of the National Academy of Sciences of the United States of America 37 29114052
2017 Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin. Proceedings of the National Academy of Sciences of the United States of America 36 28439015
2007 TopBP1 associates with NBS1 and is involved in homologous recombination repair. Biochemical and biophysical research communications 36 17765870
2022 A PARylation-phosphorylation cascade promotes TOPBP1 loading and RPA-RAD51 exchange in homologous recombination. Molecular cell 35 35597237
2020 Functions of TopBP1 in preserving genome integrity during mitosis. Seminars in cell & developmental biology 35 32912640
2004 TopBP1 localises to centrosomes in mitosis and to chromosome cores in meiosis. Chromosoma 34 15138768
2019 Common motifs in ETAA1 and TOPBP1 required for ATR kinase activation. The Journal of biological chemistry 33 30940728
2014 Interaction between Rad9-Hus1-Rad1 and TopBP1 activates ATR-ATRIP and promotes TopBP1 recruitment to sites of UV-damage. DNA repair 33 25091155
2010 Dpb11/TopBP1 plays distinct roles in DNA replication, checkpoint response and homologous recombination. DNA repair 33 21130053
2018 BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands. eLife 32 30295604
2015 High levels of TopBP1 induce ATR-dependent shut-down of rRNA transcription and nucleolar segregation. Nucleic acids research 32 25916852
2010 Function of TopBP1 in genome stability. Sub-cellular biochemistry 32 20012580
2006 Identification of a common polymorphism in the TopBP1 gene associated with hereditary susceptibility to breast and ovarian cancer. European journal of cancer (Oxford, England : 1990) 32 16930991
2011 Tethering DNA damage checkpoint mediator proteins topoisomerase IIbeta-binding protein 1 (TopBP1) and Claspin to DNA activates ataxia-telangiectasia mutated and RAD3-related (ATR) phosphorylation of checkpoint kinase 1 (Chk1). The Journal of biological chemistry 31 21502314
2011 The unstructured C-terminal tail of yeast Dpb11 (human TopBP1) protein is dispensable for DNA replication and the S phase checkpoint but required for the G2/M checkpoint. The Journal of biological chemistry 31 21956112
2021 CK2 Phosphorylation of Human Papillomavirus 16 E2 on Serine 23 Promotes Interaction with TopBP1 and Is Critical for E2 Interaction with Mitotic Chromatin and the Viral Life Cycle. mBio 30 34544280
2015 Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication. Virology 28 25666521
2013 Akt switches TopBP1 function from checkpoint activation to transcriptional regulation through phosphoserine binding-mediated oligomerization. Molecular and cellular biology 28 24081328
2023 Human Papillomavirus 16 E2 Interaction with TopBP1 Is Required for E2 and Viral Genome Stability during the Viral Life Cycle. Journal of virology 27 36840558

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