Affinage

UIMC1

BRCA1-A complex subunit RAP80 · UniProt Q96RL1

Length
719 aa
Mass
79.7 kDa
Annotated
2026-06-10
61 papers in source corpus 42 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAP80 (UIMC1) is a multivalent ubiquitin/SUMO receptor that nucleates the BRCA1-A complex at DNA double-strand breaks (DSBs) and governs the magnitude of the DNA damage response (PMID:17525340, PMID:17525341, PMID:17525342, PMID:22792303). Its tandem ubiquitin-interacting motifs (UIMs) selectively recognize K63-linked polyubiquitin chains generated by the RNF8-Ubc13 cascade, with linkage specificity arising from an inter-UIM helical linker that positions the two UIMs to simultaneously engage the proximal and distal ubiquitin moieties of K63 di-ubiquitin (PMID:18077395, PMID:19328070, PMID:19536136, PMID:22350954). A complementary SUMO-interacting motif (SIM) binds SUMO-2/3 and the hybrid SUMO-ubiquitin chains synthesized by RNF4, and CK2-dependent phosphorylation of the SIM enhances its affinity for SUMO-2; both SIM and UIM modules are required for efficient RAP80 recruitment to breaks (PMID:22689573, PMID:23211528, PMID:26719330). Through an Abraxas-interacting region, RAP80 assembles and stabilizes the Abraxas-BRCC36-MERIT40-BRCA1-BARD1 complex, in which the BRCC36 deubiquitinase counterbalances RNF8-Ubc13 ubiquitination to set a steady-state ubiquitin level at breaks (PMID:17525340, PMID:17525341, PMID:17525342, PMID:19202061, PMID:19261746, PMID:22792303). Functionally, the RAP80-BRCA1 complex restrains rather than simply promotes repair: it limits Mre11-CtIP-dependent end resection and suppresses excessive homologous recombination, and its loss causes hyper-resection, elevated HR, and chromosomal instability (PMID:21406551, PMID:21335604). RAP80 activity and abundance are tuned across the cell cycle by ATM/ATR phosphorylation at Ser205, Cdk1 phosphorylation at Ser677, USP13-reversed ubiquitination, DOT1L-mediated methylation that enables binding to ubiquitinated H2A, and APC/C-dependent destruction-box proteolysis in mitosis and G1 (PMID:18519686, PMID:17621610, PMID:22426463, PMID:23264621, PMID:28569838, PMID:39172790). Its N-terminal intrinsically disordered region drives K63-polyubiquitin-stimulated liquid-liquid phase separation that concentrates BRCA1 recruitment at breaks (PMID:37638744). RAP80 is a tumor suppressor in vivo, as RAP80-deficient mice develop B-cell lymphomas with clonal translocations, and a familial breast-cancer ΔE81 allele disrupts UIM1 structure and ubiquitin binding to impair complex recruitment (PMID:22539352, PMID:22896338, PMID:19305427, PMID:24627472).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2007 High

    Established RAP80 as the ubiquitin sensor that links K63-polyubiquitin at breaks to BRCA1 recruitment, defining the BRCA1-A complex and its checkpoint/repair role.

    Evidence Phosphopeptide affinity proteomics, reciprocal Co-IP, UIM mutagenesis, and IR-induced foci/checkpoint assays across three simultaneous papers

    PMID:17525340 PMID:17525341 PMID:17525342

    Open questions at the time
    • Did not resolve the structural basis of K63 selectivity
    • Upstream E3/E2 generating the chains not yet defined here
  2. 2007 High

    Identified the upstream RNF8-Ubc13 cascade and the Abraxas-interacting region, placing RAP80 downstream of MDC1-γH2AX-dependent ubiquitination.

    Evidence siRNA epistasis of Ubc13/RNF8, domain mapping, and foci assays

    PMID:17525341 PMID:18077395

    Open questions at the time
    • Did not address how RAP80 modulates resection or HR outcome
    • Stoichiometry of complex assembly unresolved
  3. 2009 High

    Defined the structural mechanism of K63 linkage selectivity through tandem-UIM avidity enforced by the inter-UIM helical linker.

    Evidence 2.2 Å crystal structure and NMR of tandem UIMs bound to K63 di-ubiquitin with linker-length mutants

    PMID:19328070 PMID:19536136 PMID:22350954

    Open questions at the time
    • Did not address SUMO-chain recognition
    • In vivo consequence of altered linker only partially tested
  4. 2009 High

    Showed RAP80 builds a DUB-active complex with BRCC36 and MERIT40 that antagonizes RNF8-Ubc13 ubiquitination, balancing ubiquitin levels at breaks.

    Evidence Catalytically inactive BRCC36 mutants, RNF8/BRCC36 epistasis, and complex-component knockdowns with foci/DUB readouts

    PMID:19202061 PMID:19261746

    Open questions at the time
    • Physiological substrates of the DUB at breaks incompletely defined
    • Quantitative balance point not measured
  5. 2011 High

    Reframed RAP80-BRCA1 as a restraint on repair, showing it limits CtIP-Mre11 end resection and suppresses excessive HR to preserve genome stability.

    Evidence RAP80/BRCC36 knockdown with HR reporters, RPA/ssDNA resection assays, foci kinetics, and chromosomal instability measurements

    PMID:21335604 PMID:21406551 PMID:21622030

    Open questions at the time
    • Molecular mechanism by which complex blocks resection not fully defined
    • Relationship to BRCA1 partitioning toward PALB2-BRCA2 not directly tested here
  6. 2012 High

    Added a SUMO arm: a SIM binds SUMO-2/3 and RNF4-made hybrid SUMO-ubiquitin chains, and both SIM and UIMs are needed for recruitment, integrating SUMO and ubiquitin signaling.

    Evidence In vitro affinity binding to hybrid chains, RNF4 knockdown, and SIM/UIM rescue foci assays

    PMID:22689573 PMID:23211528

    Open questions at the time
    • Relative contribution of SUMO vs ubiquitin reading in vivo unquantified
    • Identity of the SUMOylated substrates at breaks unclear
  7. 2012 Medium

    Established cell-cycle control of RAP80 abundance and activity via APC/C destruction-box proteolysis and Cdk1 Ser677 phosphorylation.

    Evidence Synchronization, Cdc20/Cdh1 knockdown, D-box mutants, in vitro Cdk1 kinase assays, and G2/M checkpoint readouts

    PMID:22426463 PMID:23264621

    Open questions at the time
    • Interplay between degradation and modification not integrated
    • Functional impact of fluctuation on repair timing not directly tested
  8. 2012 Medium

    Confirmed RAP80 as the scaffold whose loss collapses BRCA1-A complex recruitment, validated in a RAP80-null human line by reconstitution.

    Evidence RAP80-null TOV-21G cells, Co-IP, foci of complex components, and wild-type rescue

    PMID:22792303

    Open questions at the time
    • Single cell-line context
    • Quantitative scaffolding contributions of individual subunits unresolved
  9. 2012 High

    Demonstrated RAP80 is a tumor suppressor in vivo, with knockout mice developing lymphomas and IR hypersensitivity from defective complex recruitment.

    Evidence Germline knockout mice, tumor surveillance, IR sensitivity, and γH2AX/foci assays in MEFs, corroborated by an independent knockout

    PMID:22539352 PMID:22896338

    Open questions at the time
    • Tissue specificity of tumor predisposition not mechanistically explained
    • Contribution of HR suppression vs other functions to tumorigenesis unresolved
  10. 2014 High

    Provided the structural explanation for a familial breast-cancer allele, showing ΔE81 frameshifts the UIM1 N-cap and abolishes multivalent ubiquitin binding.

    Evidence NMR comparison of wild-type and ΔE81 UIM1 with ubiquitin-binding and foci assays

    PMID:19305427 PMID:24627472

    Open questions at the time
    • Disease causality at the population level not established by structure alone
    • Penetrance and modifier effects unaddressed
  11. 2015 Medium

    Defined antagonistic DUBs (USP26/USP37) that limit RAP80-BRCA1 spreading, and CK2 phosphorylation enhancing SIM-SUMO-2 specificity.

    Evidence Genetic screen with double-depletion rescue, foci/HR assays, and NMR of SUMO-2·phospho-SIM complex

    PMID:26101254 PMID:26719330

    Open questions at the time
    • Coordination of these regulators in vivo not integrated
    • Temporal sequence of phospho-SIM activation during repair unclear
  12. 2017 Medium

    Identified USP13 as an ATM-activated DUB that deubiquitinates RAP80 to promote its recruitment, with therapeutic relevance to PARP/cisplatin sensitivity.

    Evidence In vitro DUB assays, ATM-dependent phosphorylation, Co-IP, foci, and drug sensitivity assays

    PMID:28569838

    Open questions at the time
    • Specific RAP80 ubiquitination sites reversed by USP13 not mapped
    • Single lab
  13. 2022 Medium

    Extended RAP80 function to R-loop protection, preventing CtIP processing of R-loop ssDNA near breaks to enable transcription-associated end joining.

    Evidence siRNA knockdown, S9.6 R-loop imaging, CtIP epistasis, and translocation/deletion assays

    PMID:35108530

    Open questions at the time
    • Direct RAP80 binding to R-loop structures not shown
    • Mechanism of CtIP restriction at R-loops unresolved
  14. 2023 Medium

    Showed RAP80 IDR-driven, K63-polyubiquitin-stimulated phase separation concentrates BRCA1 recruitment at breaks.

    Evidence In vitro phase separation, cellular condensate imaging, IDR deletion mutants, and radiosensitivity assays

    PMID:37638744

    Open questions at the time
    • In vivo necessity of condensation distinct from binding not fully separated
    • Single lab
  15. 2024 Medium

    Added a methylation layer: DOT1L methylates RAP80 to enable binding of ubiquitinated H2A and BRCA1-A recruitment.

    Evidence In vitro methylation, MS site mapping, ubiquitinated-H2A pull-down, ChIP, and foci/radiosensitivity assays

    PMID:39172790

    Open questions at the time
    • Interplay of methylation with UIM/SIM reading not integrated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAP80's multiple, partly redundant recruitment modes (UIM, SIM, methyl-H2A reading, phase separation) and its many post-translational modifications are quantitatively coordinated in time to switch BRCA1-A from HR restraint to other repair functions remains unresolved.
  • No unified kinetic model integrating modifications and recruitment modes
  • Relative contributions of SUMO vs ubiquitin vs methylation reading not partitioned in vivo
  • Mechanism linking HR restraint to alternative end-joining/R-loop functions unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 2
Partners
ABRAXAS1BABAM1BRCA1BRCC36MDC1RNF4TRAIPUSP13
Complex memberships
BRCA1-A complexBRCC36 deubiquitinase complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 RAP80 contains tandem ubiquitin-interacting motifs (UIMs) that directly bind ubiquitin and K63-linked polyubiquitin chains at DNA double-strand breaks, and interacts with Abraxas (CCDC98) to form a BRCA1 complex (BRCA1-A complex) required for BRCA1 recruitment to DNA damage foci, G2/M checkpoint control, and DNA repair. Phosphopeptide affinity proteomics, co-immunoprecipitation, UIM domain deletion/mutation analysis, ionizing radiation-induced foci assays, siRNA knockdown with checkpoint and repair readouts Science High 17525340 17525341 17525342
2007 RAP80 recruits a complex containing BRCA1-BARD1 E3 ligase and the deubiquitinating enzyme BRCC36 to MDC1-γH2AX-dependent K6- and K63-linked ubiquitin polymers at DSBs; this complex assembly is required for cell cycle checkpoint and repair responses to ionizing radiation. Co-immunoprecipitation, ubiquitin chain-type specific binding assays, siRNA knockdown with checkpoint and foci readouts Science High 17525341
2007 RAP80 contains an Abraxas-interacting region (AIR) required for association with Abraxas, BRCA1, and BRCC36; Ubc13 (E2) and RNF8 (E3) generate K63-linked polyubiquitin chains at DNA damage sites that are recognized by RAP80 UIMs to recruit the entire BRCA1-A complex. Genetic knockdown (siRNA) of Ubc13/RNF8, domain mapping, co-immunoprecipitation, foci formation assays Proceedings of the National Academy of Sciences of the United States of America High 18077395
2009 The tandem UIMs of RAP80 achieve K63-linked polyubiquitin selectivity through 'linkage-specific avidity': the inter-UIM linker positions UIM1 and UIM2 to simultaneously engage the proximal and distal ubiquitin moieties of a K63-linked di-ubiquitin, a geometry incompatible with K48-linked chains or monoubiquitin. In vitro ubiquitin binding assays, crystal structure of RAP80 tandem UIMs bound to K63-diubiquitin (2.2 Å), inter-UIM linker length mutants, pull-down analyses Molecular Cell / The EMBO Journal High 19328070 19536136
2009 RAP80 and BRCC36 form a deubiquitinating enzyme (DUB) complex that antagonizes RNF8-Ubc13–dependent K63-ubiquitination at DSBs; BRCC36 knockdown or catalytically inactive mutant rescues 53BP1 and γH2AX ubiquitination levels following RNF8 depletion, establishing a steady-state balance of ubiquitin levels at DSBs. siRNA knockdown of BRCC36/RNF8, catalytically-inactive BRCC36 mutant expression, foci assays, ionizing radiation sensitivity assays Proceedings of the National Academy of Sciences of the United States of America High 19202061
2009 MERIT40 (C19orf62) is a RAP80-associated protein essential for BRCA1-RAP80 complex protein interactions, stability, and DSB targeting; MERIT40 is also required for RAP80-associated K63-ubiquitin DUB activity. Proteomic identification, co-immunoprecipitation, siRNA knockdown with foci and checkpoint readouts, DUB activity assays Genes & development High 19261746
2009 The crystal structure and NMR solution structure of RAP80 tandem UIMs complexed with K63-linked di-ubiquitin show that UIM1 and UIM2 each contact the Ile44 hydrophobic patch of the proximal and distal ubiquitin moieties, respectively, and the inter-UIM region forms an alpha-helix that positions the two UIMs for linkage-specific binding. X-ray crystallography (2.2 Å), pull-down with inter-UIM mutants; NMR structure determination with NOE restraints and RDC data The EMBO Journal / Journal of Biomolecular NMR High 19536136 22350954
2011 The RAP80-BRCA1 complex suppresses excessive homologous recombination (HR) at DSBs by controlling the kinetics of HR-promoting BRCA1 complexes at nuclear foci; RAP80 depletion leads to exaggerated DSB end processing, elevated HR, and chromosomal instability. siRNA knockdown of RAP80, HR assays, foci kinetics by live imaging, chromosomal instability measurement Genes & development High 21335604 21406551
2011 The BRCA1-RAP80 complex restricts Mre11-CtIP-dependent 5' end resection in S/G2 phase, thereby limiting HDR mechanisms that rely on 3' single-stranded overhangs; RAP80 or BRCC36 deficiency results in elevated end resection and increased HDR. siRNA knockdown, RPA/ssDNA foci assays, resection biochemical assays, HR reporter assays The Journal of Biological Chemistry High 21335604
2010 BRCC36 DUB activity within the RAP80 complex specifically requires Abraxas and BRCC45 interactions, distinct from its cytoplasmic BRISC complex where KIAA0157/Abro is required; BRISC deficiency enhances BRCA1-RAP80 complex formation and increases BRCA1 at DSBs. Co-immunoprecipitation, DUB activity assays, siRNA knockdown of complex components, foci assays The Journal of Biological Chemistry Medium 20656689
2012 RAP80 contains a SUMO-interacting motif (SIM) that binds SUMO2/3 conjugates; together with the tandem UIMs, the SIM-UIM-UIM motif enables binding to both K63-ubiquitin and SUMO2 conjugates, and both SIM and UIM domains are required for efficient RAP80 recruitment to DSBs. SIM identification by sequence analysis, in vitro binding assays, co-immunoprecipitation, siRNA-rescue foci assays, IR sensitivity assays The Journal of Biological Chemistry High 22689573 23211528
2012 RNF4, a SUMO-targeted ubiquitin E3 ligase, synthesizes hybrid SUMO-ubiquitin chains at DSBs; RAP80 binds these hybrid chains through its SIM (nanomolar affinity) to promote BRCA1 recruitment; RNF4 depletion impairs RAP80 and BRCA1 foci formation. In vitro binding assays with hybrid SUMO-ubiquitin chains (affinity measurements), siRNA knockdown of RNF4 with foci readouts, co-immunoprecipitation Science Signaling High 23211528
2015 NMR structure of the SUMO-2·phospho-RAP80 SIM complex shows that CK2-dependent phosphorylation of the RAP80 SIM enhances affinity and specificity for SUMO-2 via electrostatic interactions with the isoform-specific SIM recognition module of SUMO-2. NMR spectroscopy, NMR structure determination, phosphopeptide binding assays The Journal of Biological Chemistry High 26719330
2007 RAP80 directly interacts with estrogen receptor alpha (ERα) in an agonist-dependent manner through the hinge/LBD of ERα; RAP80 UIMs reduce ERα polyubiquitination and increase ERα protein levels and transcriptional activity; UIM deletion abolishes these effects without affecting ERα binding. Mammalian two-hybrid, GST pull-down, co-immunoprecipitation, siRNA knockdown, reporter assays, ubiquitination assays Nucleic Acids Research Medium 17311814
2007 RAP80 functions as an active transcriptional repressor and interacts with the retinoid-related testis-associated receptor (RTR) through its hinge domain; RAP80 competes with co-repressor N-CoR for RTR binding and inhibits RTR-N-CoR interaction. Mammalian two-hybrid, GST pull-down, co-immunoprecipitation, deletion/point mutation analysis, transcriptional reporter assays The Journal of Biological Chemistry Medium 12080054
2007 RAP80 is a target of SUMO-1 and SUMO-3 modification in intact cells; the SUMO-conjugating enzyme UBC9 interacts with RAP80 through residues 122–204; UBC9 overexpression enhances RAP80 mono- and multi-sumoylation. Yeast two-hybrid screen, co-immunoprecipitation, GST pull-down, in vivo sumoylation assays Biochemical and Biophysical Research Communications Medium 17698038
2009 ATM phosphorylates RAP80 at Ser205 in cells exposed to ionizing radiation within 5 minutes after irradiation; UV irradiation induces RAP80 Ser205 phosphorylation via ATR (not ATM); this phosphorylation is not required for IRIF formation. Phospho-specific antibody generation, ATM/ATR inhibitor treatment, immunofluorescence, kinase assays Cancer Research Medium 17621610 18519686
2009 RAP80 interacts with p53 and the E3 ubiquitin ligase HDM2 to promote HDM2-dependent p53 polyubiquitination; RAP80 is transcriptionally induced by p53 in a DNA-damage-responsive manner through a noncanonical p53 response element, forming an autoregulatory loop. Promoter analysis, co-immunoprecipitation, ubiquitination assays, siRNA knockdown with p53 target gene and apoptosis readouts The Journal of Biological Chemistry Medium 19433585
2012 RAP80 protein levels fluctuate during the cell cycle; RAP80 is degraded by APC/C(Cdc20) during mitosis and APC/C(Cdh1) during G1 phase through a conserved destruction box (D-box); knockdown of Cdc20 or Cdh1 blocks RAP80 degradation; overexpression of a D-box deletion mutant attenuates mitotic progression. Cell cycle synchronization, flow cytometry, siRNA knockdown of Cdc20/Cdh1, ubiquitination assays, D-box mutant expression Molecular Cancer Research Medium 22426463
2012 Cdk1-cyclin B1 complex phosphorylates RAP80 at Ser677; this phosphorylation occurs in M phase and is induced by ionizing radiation; Ser677Ala mutation sensitizes cells to IR and impairs G2/M checkpoint control. In vitro kinase assay, phosphopeptide-specific antibody, Ser677Ala mutant expression, IR sensitivity assays, G2/M checkpoint assays The Journal of Biological Chemistry Medium 23264621
2011 MDC1 directly binds RAP80 through its tandem BRCT domain and the UIMs of RAP80; this interaction depends on UBC13-dependent ubiquitylation of MDC1 at K1977; K1977 of MDC1 is required for RAP80 focus formation at DSBs. Co-immunoprecipitation, direct binding assay, UBC13 knockdown, MDC1 K1977 mutagenesis, foci assays DNA Repair Medium 21622030
2012 RAP80 acts as a scaffold protein for the BRCA1-A complex; loss of RAP80 (in RAP80-null TOV-21G cells) disrupts the entire complex and suppresses recruitment of BRCA1, CCDC98, NBA1, BRCC36 and BRE to DSBs; reconstitution with wild-type RAP80 rescues these defects. RAP80-null cell line identification, co-immunoprecipitation, foci assays, reconstitution experiments, IR sensitivity assay PloS ONE Medium 22792303
2012 RAP80-deficient mice develop B-cell lymphomas with clonal chromosomal translocations and are hypersensitive to ionizing radiation; RAP80-null MEFs show impaired DSB repair due to loss of BRCA1-A complex recruitment to damage sites. RAP80 knockout mouse generation, tumor surveillance, IR sensitivity assays, γH2AX/foci assays in MEFs The Journal of Biological Chemistry High 22539352 22896338
2015 USP26 and USP37 are recruited to DSBs where they remove RNF168-induced ubiquitin conjugates, limiting RAP80-BRCA1 spreading from DSBs; their depletion impairs HR, and this defect is rescued by simultaneous RAP80 depletion, placing USP26/USP37 as antagonists of RAP80-mediated BRCA1 sequestration. Genetic screen, siRNA knockdown epistasis (single and double depletions), foci assays, HR reporter assays Nucleic Acids Research Medium 26101254
2015 TIP60-mediated H4K16 acetylation prevents 53BP1 binding to H4K20me2; Fanconi anemia pathway inactivation impairs FANCD2 monoubiquitination and TIP60 relocalization, leading to aberrant chromatin accumulation of RAP80 and 53BP1 that impairs resection and HR. siRNA knockdown, ChIP, histone modification analysis, HR assays Nucleic Acids Research Medium 26446986
2016 TRAIP/RNF206 is a novel RAP80-interacting protein that acts upstream of RAP80; TRAIP depletion impairs RAP80 and BRCA1 accumulation at DNA lesions; TRAIP localizes to damage sites through direct interaction with RNF20-RNF40 via its C-terminus, while its N-terminus mediates RAP80 binding. Co-immunoprecipitation, siRNA knockdown with foci readouts, domain mapping, in vitro binding assays Nature Communications Medium 26781088
2017 USP13 is phosphorylated by ATM following DNA damage and deubiquitinates RAP80, promoting RAP80 recruitment to DSBs and proper DDR; USP13 depletion or inhibition sensitizes ovarian cancer cells to cisplatin and PARP inhibitors. Co-immunoprecipitation, in vitro deubiquitination assays, ATM inhibitor treatment, siRNA knockdown, foci assays, drug sensitivity assays Nature Communications Medium 28569838
2009 The inter-UIM linker length of RAP80 is a critical determinant of K63-linked polyubiquitin binding affinity; modifying linker length by insertion or deletion changes binding affinity and impairs translocation to DSBs. In vitro GST pull-down assays with linker mutants, foci assays BMB Reports Low 19944020
2009 The RAP80 ΔE81 deletion mutant (c.241-243delGAA) found in familial breast cancer cases displays significantly reduced ubiquitin binding and DSB localization, impairs BRCA1 and Abraxas DSB recruitment, and increases chromosomal aberrations. Ubiquitin binding assays, foci formation assays, chromosomal aberration analysis, expression of ΔE81 allele Oncogene Medium 19305427 24627472
2014 NMR spectroscopy shows that the ΔE81 deletion causes a structural frameshift in the N-cap of the first UIM alpha-helix, abolishing multivalent polyubiquitin binding by disrupting favorable electrostatic interactions between UIM1 and ubiquitin. NMR spectroscopy, structural comparison of wild-type and ΔE81 UIM1 The Journal of Biological Chemistry High 24627472
2020 BRCA1 PARsylation and RAP80-bound BRCA1 together regulate normal interaction of BRCA1 with CtIP and BACH1 in nuclear foci; simultaneous loss of RAP80 and failure of BRCA1 PARsylation results in dysregulated accumulation of BRCA1 complexes in foci, hyper-recombination, and gross chromosomal disorder. Genetic depletion (siRNA/knockout), PARP inhibition, HR assays, foci kinetics, chromosomal instability measurement Proceedings of the National Academy of Sciences of the United States of America Medium 31932421
2014 FANCG undergoes K63-linked polyubiquitination in response to DNA damage, which is required for its interaction with the RAP80-BRCA1 complex and subsequent HR repair of ICLs; BRCC36 deubiquitinates K63-ubiquitinated FANCG in vitro and in vivo. Co-immunoprecipitation, in vitro ubiquitination/deubiquitination assays, FANCG 3KR mutant expressing cells, HR reporter assays Oncogene Medium 25132264
2017 RAP80 binds the mitochondrial protein p32 through its arginine-rich C-terminal domain; a subset of RAP80 localizes to mitochondria; RAP80 deficiency reduces p32 protein levels and p32-dependent mitochondrial proteins (Rieske, COX1), reducing mitochondrial membrane potential and oxygen consumption. Yeast two-hybrid screening, co-immunoprecipitation, subcellular fractionation/mitochondrial localization, siRNA knockdown with mitochondrial function readouts Biochemical and Biophysical Research Communications Low 28842250
2022 RAP80 prevents CtIP-mediated nucleolytic processing of ssDNA in R-loops near DSBs, thereby promoting efficient DSB repair via transcription-associated end joining dependent on BRCA1, Polθ, and LIG1/3; RAP80 depletion increases chromosome translocations and deletions due to unscheduled R-loop ssDNA processing. siRNA knockdown, R-loop detection (S9.6 immunofluorescence), CtIP epistasis, chromosomal translocation and deletion assays Cell Reports Medium 35108530
2023 RAP80 undergoes liquid-liquid phase separation (LLPS) at DSBs through an intrinsically disordered region (IDR) at its N-terminus; K63-linked polyubiquitin chains at DSBs strongly enhance RAP80 phase separation; abolishing RAP80 condensation suppresses BRCA1 foci formation and increases radiosensitivity. In vitro phase separation assays, cellular condensate imaging, IDR deletion mutants, radiosensitivity assays Nucleic Acids Research Medium 37638744
2024 DOT1L methyltransferase is recruited to chromatin after DNA damage and methylates RAP80 at multiple lysines; methylated RAP80 binds ubiquitinated H2A and triggers BRCA1-A complex recruitment to DSBs; DOT1L inhibition or mutation of RAP80 methylation sites reduces BRCA1 recruitment and enhances radiosensitivity. In vitro methylation assays, methylation site identification by MS, Co-IP, ChIP, ubiquitinated H2A pull-down, siRNA/inhibitor knockdown with foci and radiosensitivity readouts Proceedings of the National Academy of Sciences of the United States of America Medium 39172790
2010 RAP80 performs a BRCA1-independent repair function specific to topoisomerase II inhibitor (etoposide) damage; RAP80-null DT40 cells are proficient in HR and NHEJ but sensitive to etoposide; RAP80/BRCA1 double knockout cells are more sensitive to etoposide than BRCA1 single knockouts. Genetic disruption of RAP80 in DT40 cells, single and double mutant analysis, drug sensitivity assays (etoposide, other agents), HR and NHEJ assays Cancer Research Medium 20959489
2026 SENP3 deSUMOylates RAP80 to facilitate timely RAP80 dissociation from DSB sites during later stages of repair; SENP3 depletion causes aberrant prolonged RAP80 SUMOylation and retention at damage foci, impairing HR repair progression. Co-immunoprecipitation, in vivo SUMOylation assays, siRNA knockdown of SENP3, foci assays, HR and IR sensitivity assays Acta Biochimica et Biophysica Sinica Low 42093510

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science (New York, N.Y.) 579 17525340
2007 RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science (New York, N.Y.) 565 17525341
2007 Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science (New York, N.Y.) 462 17525342
2007 Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proceedings of the National Academy of Sciences of the United States of America 357 18077395
2011 RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci. Genes & development 199 21406551
2011 The BRCA1-RAP80 complex regulates DNA repair mechanism utilization by restricting end resection. The Journal of biological chemistry 185 21335604
2009 The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proceedings of the National Academy of Sciences of the United States of America 184 19202061
2009 Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of rap80. Molecular cell 184 19328070
2009 Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by tandem UIMs of RAP80. The EMBO journal 173 19536136
2012 RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage. Science signaling 154 23211528
2007 The ubiquitin-interacting motif containing protein RAP80 interacts with BRCA1 and functions in DNA damage repair response. Cancer research 142 17621610
2009 MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes & development 125 19261746
2017 USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response. Nature communications 100 28569838
2013 Co-operation of BRCA1 and POH1 relieves the barriers posed by 53BP1 and RAP80 to resection. Nucleic acids research 97 24013561
2010 Differential regulation of JAMM domain deubiquitinating enzyme activity within the RAP80 complex. The Journal of biological chemistry 72 20656689
2015 Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells. Nucleic acids research 69 26446986
2008 RAP80 and RNF8, key players in the recruitment of repair proteins to DNA damage sites. Cancer letters 66 18550271
2012 Rap80 protein recruitment to DNA double-strand breaks requires binding to both small ubiquitin-like modifier (SUMO) and ubiquitin conjugates. The Journal of biological chemistry 65 22689573
2015 The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80. Nucleic acids research 64 26101254
2009 Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function. Oncogene 54 19305427
2016 TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage. Nature communications 41 26781088
2002 RAP80, a novel nuclear protein that interacts with the retinoid-related testis-associated receptor. The Journal of biological chemistry 41 12080054
2012 RAP80 protein is important for genomic stability and is required for stabilizing BRCA1-A complex at DNA damage sites in vivo. The Journal of biological chemistry 40 22539352
2015 Molecular Basis for Phosphorylation-dependent SUMO Recognition by the DNA Repair Protein RAP80. The Journal of biological chemistry 36 26719330
2007 Ubiquitin-interaction motifs of RAP80 are critical in its regulation of estrogen receptor alpha. Nucleic acids research 29 17311814
2012 Cdk1 protein-mediated phosphorylation of receptor-associated protein 80 (RAP80) serine 677 modulates DNA damage-induced G2/M checkpoint and cell survival. The Journal of biological chemistry 27 23264621
2012 RAP80 is critical in maintaining genomic stability and suppressing tumor development. Cancer research 25 22896338
2007 RAP80 interacts with the SUMO-conjugating enzyme UBC9 and is a novel target for sumoylation. Biochemical and biophysical research communications 25 17698038
2023 RAP80 phase separation at DNA double-strand break promotes BRCA1 recruitment. Nucleic acids research 24 37638744
2014 Two biomarker-directed randomized trials in European and Chinese patients with nonsmall-cell lung cancer: the BRCA1-RAP80 Expression Customization (BREC) studies. Annals of oncology : official journal of the European Society for Medical Oncology 24 25164908
2012 Degradation of human RAP80 is cell cycle regulated by Cdc20 and Cdh1 ubiquitin ligases. Molecular cancer research : MCR 23 22426463
2017 RAP80, ubiquitin and SUMO in the DNA damage response. Journal of molecular medicine (Berlin, Germany) 20 28681078
2011 Tubulin, BRCA1, ERCC1, Abraxas, RAP80 mRNA expression, p53/p21 immunohistochemistry and clinical outcome in patients with advanced non small-cell lung cancer receiving first-line platinum-gemcitabine chemotherapy. Lung cancer (Amsterdam, Netherlands) 20 21529986
2008 RAP80 responds to DNA damage induced by both ionizing radiation and UV irradiation and is phosphorylated at Ser 205. Cancer research 19 18519686
2014 K63-linked ubiquitination of FANCG is required for its association with the Rap80-BRCA1 complex to modulate homologous recombination repair of DNA interstand crosslinks. Oncogene 17 25132264
2009 A regulatory loop composed of RAP80-HDM2-p53 provides RAP80-enhanced p53 degradation by HDM2 in response to DNA damage. The Journal of biological chemistry 17 19433585
2008 Germline RAP80 mutations and susceptibility to breast cancer. Breast cancer research and treatment 16 18306035
2016 Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy. The pharmacogenomics journal 15 27779244
2011 MDC1 is ubiquitylated on its tandem BRCT domain and directly binds RAP80 in a UBC13-dependent manner. DNA repair 15 21622030
2008 Analysis of the genes coding for the BRCA1-interacting proteins, RAP80 and Abraxas (CCDC98), in high-risk, non-BRCA1/2, multiethnic breast cancer cases. Breast cancer research and treatment 15 18695986
2020 RAP80 and BRCA1 PARsylation protect chromosome integrity by preventing retention of BRCA1-B/C complexes in DNA repair foci. Proceedings of the National Academy of Sciences of the United States of America 13 31932421
2024 DOT1L-mediated RAP80 methylation promotes BRCA1 recruitment to elicit DNA repair. Proceedings of the National Academy of Sciences of the United States of America 12 39172790
2016 RAP80 regulates epithelial-mesenchymal transition related with metastasis and malignancy of cancer. Cancer science 12 26748910
2012 Loss of BRCA1-A complex function in RAP80 null tumor cells. PloS one 12 22792303
2012 NMR analysis of Lys63-linked polyubiquitin recognition by the tandem ubiquitin-interacting motifs of Rap80. Journal of biomolecular NMR 11 22350954
2009 Mutation screening of the MERIT40 gene encoding a novel BRCA1 and RAP80 interacting protein in breast cancer families. Breast cancer research and treatment 11 19572197
2022 RAP80 suppresses the vulnerability of R-loops during DNA double-strand break repair. Cell reports 10 35108530
2011 Recruitment of proteins to DNA double-strand breaks: MDC1 directly recruits RAP80. Cell cycle (Georgetown, Tex.) 10 21857162
2010 RAP80 acts independently of BRCA1 in repair of topoisomerase II poison-induced DNA damage. Cancer research 9 20959489
2020 FANCJ compensates for RAP80 deficiency and suppresses genomic instability induced by interstrand cross-links. Nucleic acids research 8 32797166
2014 Molecular basis for impaired DNA damage response function associated with the RAP80 ΔE81 defect. The Journal of biological chemistry 7 24627472
2009 The linker connecting the tandem ubiquitin binding domains of RAP80 is critical for lysine 63-linked polyubiquitin-dependent binding activity. BMB reports 7 19944020
2019 RAP80 expression in breast cancer and its relationship with apoptosis in breast cancer cells. OncoTargets and therapy 6 30705591
2018 Association between EGFR mutation and expression of BRCA1 and RAP80 in non-small cell lung cancer. Oncology letters 6 30008919
2013 Structural and functional implication of RAP80 ΔGlu81 mutation. PloS one 6 24039796
2007 RAP80/UIMC1 as cancer-associated antigen: alternative splice variants and their immunogenicity. Cancer letters 5 17562356
2017 RAP80 binds p32 to preserve the functional integrity of mitochondria. Biochemical and biophysical research communications 4 28842250
2012 Induction of pancreatic cancer cell apoptosis and enhancement of gemcitabine sensitivity by RAP80 siRNA. Digestive diseases and sciences 4 22573342
2026 SENP3 regulates DNA damage repair by downregulating RAP80 SUMOylation. Acta biochimica et biophysica Sinica 0 42093510
2017 Low RAP80 mRNA expression correlates with shorter survival in sporadic high-grade serous ovarian carcinoma. The International journal of biological markers 0 27443420
2016 [Chinese multicenter randomized trial of customized chemotherapy based on BRCA1 (breast cancer susceptibility gene 1)-RAP80 (receptor-associated protein 80) mRNA expression in advanced non-small cell lung cancer (NSCLC) patients]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 0 27998448

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