Affinage

TP53BP1

TP53-binding protein 1 · UniProt Q12888

Length
1972 aa
Mass
213.6 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

53BP1 is a central effector of the DNA double-strand break (DSB) response that governs repair-pathway choice by promoting non-homologous end joining (NHEJ) and suppressing homologous recombination (HR) end-resection (PMID:11238909, PMID:23727112, PMID:30022168, PMID:30046110). It is recruited to break-flanking chromatin through bivalent histone recognition: its tandem Tudor domain reads H4K20me2 (pre-established by SETD8/SUV420 and reinforced locally by MMSET, with replication-coupled dilution of this mark limiting S-phase binding) (PMID:21293379, PMID:23329852, PMID:28564601), while its UDR motif engages RNF168-dependent H2AK15ub, and RNF168 additionally K63-ubiquitylates 53BP1 to drive initial recruitment (PMID:24324146, PMID:33188174). This recruitment is gated by chromatin acetylation state — H4K16 deacetylation and H4K16me1 favor binding whereas H4K16 acetylation and CBP-mediated acetylation of the UDR motif block it (PMID:23329852, PMID:29190394, PMID:31612207) — and by TIRR, which directly masks the Tudor H4K20me2-binding surface until ATM phosphorylation and RIF1 dissociate the complex (PMID:28241136, PMID:29844495, PMID:29967538). Upon damage, ATM phosphorylation of N-terminal S/TQ sites creates phosphopeptide docking sites that recruit RIF1 (via LxL-phospho motif recognition) and, through distinct sites, PTIP, partitioning 53BP1's anti-recombination and class-switch functions (PMID:23727112, PMID:35216668, PMID:27462418). RIF1 in turn assembles the shieldin complex (REV7-SHLD1-SHLD2-SHLD3) on ssDNA and recruits CST-Polα-primase to fill in resected ends and counteract resection, the activity that confers PARP-inhibitor sensitivity in BRCA1-deficient cells (PMID:30022168, PMID:30046110, PMID:30022158, PMID:35027730, PMID:37306046). Beyond repair-pathway choice, 53BP1 amplifies p53 transcriptional output through tandem-BRCT bivalent binding of p53 and USP28 and through Tudor recognition of p53K382me2, undergoes liquid-liquid phase separation to concentrate repair and signaling factors, sequesters under-replicated DNA in G1 nuclear bodies to control replication timing, and maintains heterochromatin integrity via LLPS with HP1α (PMID:27546791, PMID:31267591, PMID:30804506, PMID:35042897). Its chromatin levels are tightly tuned by an extensive set of post-translational regulators including SPOP/TRABID-controlled K29-linked ubiquitination, RNF146/NUDT16-controlled ADP-ribosylation-coupled degradation, and PRMT5 methylation (PMID:34144977, PMID:31911551, PMID:37002234).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2001 High

    Established 53BP1 as an ATM-dependent DNA damage response factor, framing it as an early actor downstream of break-sensing kinase signaling.

    Evidence Immunofluorescence and phosphorylation assays in Xenopus and human AT cells with ATM inhibition

    PMID:11238909

    Open questions at the time
    • Did not identify the chromatin mark or recruitment receptor
    • Functional consequence for repair-pathway choice not yet defined
  2. 2009 Medium

    Placed PTIP in the recruitment hierarchy as a factor acting downstream of RNF8 and upstream of 53BP1 foci formation, beginning to order the signaling cascade.

    Evidence siRNA knockdown and IRIF analysis with phosphorylation assays

    PMID:19414588

    Open questions at the time
    • Direct binding interface to 53BP1 not defined
    • Single-lab epistasis
  3. 2011 High

    Identified the histone-mark basis of recruitment by showing MMSET deposits H4K20 methylation at breaks to license 53BP1 accumulation.

    Evidence ChIP, Co-IP, siRNA knockdown, immunofluorescence

    PMID:21293379

    Open questions at the time
    • Relative contribution of de novo versus pre-existing methylation unresolved
  4. 2013 High

    Resolved that recruitment depends on a pre-existing H4K20me2 landscape revealed by H4K16 deacetylation, and that distinct phospho-dependent partners (RIF1 versus PTIP) split 53BP1's repair functions.

    Evidence ChIP/HDAC inhibitor studies and phosphomutant knock-in with CSR and genome-stability readouts

    PMID:23329852 PMID:23727112

    Open questions at the time
    • Downstream resection-suppressing effectors of RIF1 not yet identified
    • Reconciling MMSET de novo methylation with pre-existing mark requirement
  5. 2013 High

    Showed RNF168 also directly K63-ubiquitylates 53BP1 to drive its initial recruitment, adding a ubiquitin layer to the histone-reading model.

    Evidence Co-IP, ubiquitination assays, immunofluorescence with RNF168 loss

    PMID:24324146

    Open questions at the time
    • Site of ubiquitination on 53BP1 and reader of the modification not defined
  6. 2015 High

    Extended 53BP1 function beyond static recruitment to promoting damaged-chromatin mobility, linking it to the cytoskeleton and nuclear envelope.

    Evidence Live-cell DSB tracking with LINC and kinesin depletion and microtubule disruption

    PMID:26544937

    Open questions at the time
    • Molecular bridge from 53BP1 to the LINC complex not defined
  7. 2016 High

    Separated 53BP1's p53-amplifying transcriptional function (via oligomerization and BRCT-mediated p53/USP28 binding) from its DSB-repair function.

    Evidence Domain-deletion mutants, Co-IP, reporter assays, ChIP, cell-cycle analysis

    PMID:27546791

    Open questions at the time
    • Structural basis of bivalent BRCT engagement not resolved
  8. 2017 High

    Defined TIRR as a direct negative regulator masking the Tudor H4K20me2-binding surface, establishing a chromatin-binding checkpoint released by ATM/RIF1.

    Evidence Co-IP, biochemical binding, siRNA, ATM inhibition

    PMID:28241136

    Open questions at the time
    • Atomic mechanism of masking awaited structural work
    • Trigger for TIRR release beyond RIF1 unclear
  9. 2017 High

    Demonstrated replication-coupled dilution of H4K20me2 as an intrinsic cell-cycle switch limiting 53BP1 binding on newly replicated chromatin.

    Evidence Cell synchronization, BrdU pulse-chase, chromatin fractionation, H4K20me2 ChIP

    PMID:28564601

    Open questions at the time
    • Interplay with BRCA1-mediated suppression not fully integrated
  10. 2018 High

    Provided the atomic and mechanistic basis of TIRR inhibition, including a steric arginine/histidine block and RNA-triggered displacement.

    Evidence X-ray crystallography, mutagenesis, RNA-binding and cellular recruitment assays

    PMID:29844495 PMID:29967538

    Open questions at the time
    • Identity and regulation of physiological displacing RNAs not defined
  11. 2018 High

    Identified the shieldin complex and downstream CST-Polα-primase as the resection-counteracting effectors of 53BP1-RIF1, explaining PARP-inhibitor resistance in BRCA1-deficient cells.

    Evidence BioID, Co-IP, ssDNA binding, genetic epistasis, CSR and PARPi sensitivity assays

    PMID:30022158 PMID:30022168 PMID:30046110

    Open questions at the time
    • Direct RIF1-shieldin contact not yet mapped at this stage
  12. 2018 High

    Showed that CBP-mediated acetylation of the UDR motif and HDAC2 counter-deacetylation constitute an acetylation switch controlling nucleosome engagement.

    Evidence Mass spectrometry site mapping, Co-IP, mutagenesis, PARPi sensitivity

    PMID:29190394

    Open questions at the time
    • Signals driving CBP versus HDAC2 balance at breaks not defined
  13. 2019 High

    Established that 53BP1 forms preformed nucleoplasmic dimers that oligomerize upon sequential H2AK15ub/H4K20me2 recognition, and that resulting compartments are phase-separated condensates amplifying p53.

    Evidence FFS in living cells, optoDroplet assays, AsiSI-inducible DSBs, p53 target expression

    PMID:31267591 PMID:33188174

    Open questions at the time
    • Quantitative role of LLPS in repair efficiency versus signaling not separated
  14. 2019 High

    Revealed a non-repair role for 53BP1 nuclear bodies in restraining replication of under-replicated loci to enable error-free RAD52 repair.

    Evidence Live imaging, DNA fiber assay, siRNA, genetic epistasis

    PMID:30804506

    Open questions at the time
    • Mechanism by which 53BP1-NBs delay replication timing not defined
  15. 2019 Medium

    Refined recruitment chemistry by showing H4K16me1 deposited by GLP enhances the 53BP1-H4K20me2 interaction during the DDR.

    Evidence Mass spectrometry, Co-IP, ChIP, siRNA, NHEJ reporter

    PMID:31612207

    Open questions at the time
    • Single lab; structural basis of H4K16me1 enhancement not resolved
  16. 2019 High

    Dissected two separable anti-recombination steps — a PTIP-dependent pre-resection block and a RIF1/shieldin post-resection block on RAD51 loading.

    Evidence Mouse knock-in genetics, RPA/RAD51 foci, END-seq, epistasis

    PMID:31653568

    Open questions at the time
    • Molecular target of the PTIP-dependent block not identified
  17. 2020 Medium

    Mapped opposing modification cycles regulating 53BP1 levels: PRMT5 methylation stabilizes it, while ADP-ribosylation primes RNF146/NUDT16-controlled degradation.

    Evidence In vitro methylation/de-ADP-ribosylation, MS, Co-IP, ubiquitination, NHEJ reporters

    PMID:31911551 PMID:32759981

    Open questions at the time
    • Single-lab studies; in vivo relevance of each modification not established
    • Interplay between the two modification cycles unknown
  18. 2020 Medium

    Identified effector and regulatory partners refining checkpoint output: LC8/DYNLL1 as a 53BP1-dependent checkpoint effector, PP5 as a 53BP1 phosphatase, and 53BP1 action at stressed replication forks.

    Evidence Laser microirradiation, Y2H/Co-IP, DNA fiber, ATR-Chk1 assays

    PMID:19176521 PMID:29378830 PMID:30982887

    Open questions at the time
    • Single-lab interactions without reciprocal structural validation
    • Direct molecular role of 53BP1 at forks not defined
  19. 2021 High

    Established cell-cycle-gated chromatin extraction of 53BP1 via ATM-phosphorylated SPOP-mediated K29 ubiquitination and VCP/p97, and showed AHNAK restrains its oligomerization, integrating repair-choice and p53 control.

    Evidence SPOP crystal structures, ubiquitination/p97 assays, FRAP, PLA, p53 target expression

    PMID:33961796 PMID:34144977

    Open questions at the time
    • How SPOP and AHNAK are coordinated with damage timing not resolved
  20. 2021 Medium

    Showed TIRR also gates 53BP1's p53 function by blocking Tudor-p53K382me2 binding, and that Lamin B1 and AMPK regulate 53BP1 localization and recruitment.

    Evidence Co-IP, biochemical binding, gene expression, in vitro kinase assay, NHEJ assays

    PMID:33596428 PMID:33961797 PMID:34452908

    Open questions at the time
    • Several single-lab interactions awaiting independent confirmation
    • Physiological weighting of Lamin B1/AMPK control unclear
  21. 2022 High

    Defined the molecular grammar of RIF1 recruitment (LxL-phospho motifs) and identified an alternative RIF1-dependent shieldin recruitment route, and established a 53BP1-HP1α LLPS axis maintaining heterochromatin.

    Evidence Peptide-binding, mutagenesis, IRIF/CSR assays, optoDroplet and heterochromatin repeat analysis

    PMID:35042897 PMID:35216668

    Open questions at the time
    • Nature of the alternative shieldin recruitment mode not defined
    • HP1α LLPS work from single lab
  22. 2022 High

    Pinpointed CST-Polα-primase as the dominant shieldin effector in BRCA1-deficient cells and identified SUMO-dependent ZMYM2 as a restrictor of 53BP1 enabling BRCA1-mediated HR.

    Evidence CST tethering, SHLD1 domain mutants, HR reporters, SUMO-binding mutants, PARPi sensitivity

    PMID:35027730 PMID:35253893

    Open questions at the time
    • Context-specific CST-independent shieldin functions incompletely mapped
  23. 2023 Medium

    Completed key recruitment connections and added external regulation: a predicted/validated RIF1-SHLD3 contact bridging signaling to shieldin, ESCO2/cohesin-dependent chromatin remodeling enabling 53BP1 microdomains, TRABID DUB control of K29 ubiquitination, and viral suppression of 53BP1 via lncRNA interference.

    Evidence AlphaFold2 plus pulldown, ChIP/MS, K29-specific (de)ubiquitination assays, SARS-CoV-2 infection models

    PMID:36894671 PMID:37002234 PMID:37306046 PMID:37377435

    Open questions at the time
    • Single-lab findings
    • Mechanism of lncRNA-53BP1 coupling not biochemically defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many competing modification cycles (phosphorylation, K63/K29/K48 ubiquitination, acetylation, ADP-ribosylation, methylation), condensate formation, and cell-cycle cues are quantitatively integrated to set 53BP1 chromatin dwell time and repair-pathway choice in vivo remains unresolved.
  • No unified quantitative model linking PTM state to LLPS and resection control
  • Physiological hierarchy among redundant recruitment/eviction factors unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 7 GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 3 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-69306 DNA Replication 3
Partners
AHNAKHP1APTIPRIF1RNF168SPOPTIRRUSP28
Complex memberships
shieldin (REV7-SHLD1-SHLD2-SHLD3)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 53BP1 undergoes rapid phosphorylation and relocalization to nuclear foci after DNA damage (gamma-ray irradiation). ATM kinase activity is required for this response; in AT cells lacking ATM, irradiation-induced relocalization and phosphorylation of 53BP1 are impaired. Xenopus 53BP1 (XL53BP1) is hyperphosphorylated after X-ray irradiation in an ATM-dependent manner. Immunofluorescence microscopy, phosphorylation assays, ATM inhibitor treatment, AT cell lines Molecular and cellular biology High 11238909
2011 MMSET (NSD2/WHSC1) histone methyltransferase is recruited to DSBs via the γH2AX-MDC1 pathway (through interaction of MDC1 BRCT domain with phosphorylated Ser102 of MMSET), where it catalyzes local H4K20 methylation at break sites, which in turn facilitates 53BP1 recruitment. Downregulation of MMSET decreases H4K20 methylation at DSBs and reduces 53BP1 accumulation. ChIP, co-immunoprecipitation, siRNA knockdown, immunofluorescence Nature High 21293379
2013 53BP1 promotes productive immunoglobulin class switch recombination (CSR) through a phosphorylation-dependent interaction with PTIP, and suppresses mutagenic DNA repair through RIF1. A 53BP1 phosphomutant (53BP18A) with alanine substitutions of the eight most N-terminal S/TQ sites recruits RIF1 but fails to recruit PTIP to DSBs; disruption of PTIP phenocopies 53BP18A, demonstrating that distinct phospho-dependent interactions mediate these two functions. Phosphomutant knock-in, immunofluorescence, Co-IP, CSR assay, genomic stability assays Cell High 23727112
2013 H4K16 acetylation antagonizes 53BP1 binding to H4K20me2; DNA damage induces transient, localized H4 deacetylation (at H4K16) that facilitates 53BP1 foci formation and NHEJ. 53BP1 foci assemble primarily on H4K20me2 established prior to DNA damage by SETD8 and SUV420 methyltransferases rather than de novo methylation by MMSET. Chromatin immunoprecipitation, histone modification analysis, HDAC inhibitor treatment, siRNA knockdown, immunofluorescence Journal of molecular cell biology High 23329852
2013 RNF168 mediates K63-linked ubiquitylation of 53BP1, which is required for the initial recruitment of 53BP1 to DNA double-strand break sites and for its function in DNA damage repair, checkpoint activation, and genomic integrity. Co-immunoprecipitation, ubiquitination assays, immunofluorescence, RNF168 knockdown/knockout Proceedings of the National Academy of Sciences of the United States of America High 24324146
2015 53BP1 promotes increased mobility of damaged chromatin (DSBs) through the LINC complex (SUN1/2, Nesprin-4) and dynamic microtubules. This mobility promotes NHEJ of dysfunctional telomeres and contributes to DSB mis-rejoining in BRCA1-deficient cells. Live-cell imaging of telomere-based DSB tracking, siRNA depletion of SUN1/2 and kinesin motors, microtubule depolymerization Cell High 26544937
2016 53BP1 stimulates p53-dependent gene transactivation and repression events via two separable mechanisms: (1) auto-oligomerization and (2) tandem-BRCT domain-mediated bivalent interactions with p53 and the deubiquitinase USP28. Loss of these activities impairs p53-dependent cell-cycle checkpoint and exit responses. The 53BP1-USP28 cooperation is essential for normal p53-promoter element interactions but dispensable for 53BP1's DSB repair regulation. Domain deletion mutants, Co-IP, reporter assays, ChIP, cell cycle analysis Molecular cell High 27546791
2017 TIRR (Tudor-interacting repair regulator) directly binds the tandem Tudor domain of 53BP1 and masks its H4K20me2-binding motif, preventing 53BP1 localization to DSBs. Upon DNA damage, ATM phosphorylates 53BP1 and recruits RIF1 to dissociate the 53BP1-TIRR complex. Overexpression of TIRR blocks 53BP1 function; depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction. Co-IP, immunofluorescence, siRNA knockdown, ATM inhibitor treatment, biochemical binding assays Nature High 28241136
2017 Replication-coupled dilution of H4K20me2 on newly replicated chromatin limits 53BP1 accumulation at DSBs in S-phase cells. Premature maturation of post-replicative chromatin restores H4K20me2 and rescues 53BP1 accumulation on replicated chromatin, demonstrating that H4K20me2 availability is an inbuilt cell-cycle-regulated mechanism for 53BP1 chromatin binding. Cell synchronization, immunofluorescence, BrdU pulse-chase, chromatin fractionation, H4K20me2 ChIP Cell reports High 28564601
2018 53BP1 recruits the shieldin complex (SHLD1/C20orf196, SHLD2/FAM35A, SHLD3/CTC-534A2.2, REV7) to DSB sites in a RIF1-dependent manner. SHLD2 binds single-stranded DNA via OB-fold domains. Loss of shieldin impairs NHEJ, leads to defective immunoglobulin class switching, and causes hyper-resection; shieldin mutations cause resistance to PARP inhibitors in BRCA1-deficient cells by restoring HR. Proximity labeling (BioID), Co-IP, ssDNA binding assays, genetic epistasis, class switch recombination assay, PARP inhibitor sensitivity Nature High 30022168 30046110
2018 CST (CTC1-STN1-TEN1) complex interacts with shieldin and localizes with DNA polymerase α (Polα) to sites of DNA damage in a 53BP1- and shieldin-dependent manner. CST-Polα fill-in synthesis acts as a downstream effector of 53BP1-RIF1-shieldin to counteract resection; depletion of CST increases resection and in BRCA1-deficient cells, CST blocks RAD51 loading. Co-IP, immunofluorescence, siRNA depletion, BrdU incorporation, PARP inhibitor sensitivity assays Nature High 30022158
2018 Crystal structure of TIRR in complex with the 53BP1 tandem Tudor domain at 1.76 Å resolution reveals that the N-terminal region (residues 10-24) and L8-loop of TIRR interact with 53BP1 Tudor through three loops (L1, L3, and L1'), sterically blocking H4K20me2 binding. A TIRR histidine (H106) absent from TIRR homolog Nudt16 is essential for 53BP1 Tudor binding. X-ray crystallography, in vitro binding assays, mutagenesis, cellular assays Nature communications High 29844495
2018 X-ray crystal structures of TIRR and a designer protein bound to 53BP1 reveal that an arginine residue in TIRR blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of-function mutation that abolishes TIRR-mediated regulation renders 53BP1 hyperactive in response to DSBs. TIRR-interacting RNA molecules relieve 53BP1 inhibition by displacing TIRR. X-ray crystallography, mutagenesis, RNA binding assays, cellular recruitment assays Nature structural & molecular biology High 29967538
2018 CBP-mediated acetylation of 53BP1 at K1626/K1628 in the UDR motif disrupts the interaction between 53BP1 and nucleosomes, blocking 53BP1 recruitment and its downstream factors PTIP and RIF1 to DSBs. HDAC2 deacetylates 53BP1 to counterbalance this. Hyperacetylation of 53BP1 mimics 53BP1 depletion in restoring PARP inhibitor resistance in BRCA1-deficient cells. Mass spectrometry (acetylation site mapping), Co-IP, immunofluorescence, mutagenesis, PARP inhibitor sensitivity assays Nucleic acids research High 29190394
2019 53BP1-marked repair compartments exhibit liquid-like behavior: droplet dynamics (fusion/fission), sensitivity to osmotic pressure, temperature, salt, and hydrophobic interaction disruption. Phase separation of 53BP1 is demonstrated by optoDroplet experiments. Tumor suppressor p53 is enriched within 53BP1 optoDroplets, and conditions disrupting 53BP1 phase separation impair 53BP1-dependent induction of p53 and p53 target gene expression. Live-cell microscopy, CRISPR/Cas9 endogenous tagging, optoDroplet assay, osmotic/chemical perturbation, p53 target gene expression The EMBO journal High 31267591
2019 53BP1 nuclear bodies (53BP1-NBs) formed in G1 daughter cells at under-replicated DNA loci restrain replication of the embedded genomic loci until late S phase, enabling RAD52-mediated repair of UR-DNA lesions. Absence of 53BP1-NBs causes premature replication and genotoxic RAD51-mediated recombination. Live-cell imaging, FACS, DNA fiber assay, siRNA knockdown, genetic epistasis Nature cell biology High 30804506
2019 53BP1 exerts two separable anti-recombination functions: (1) a PTIP-dependent block upstream of resection (enabling DNA2-dependent end resection) and (2) a RIF1/shieldin-dependent post-resection block that inhibits PALB2/RAD51 loading via RNF168. PTIP mutation (S25A) allows resection but not RAD51 loading due to shieldin activity. Forced PALB2 targeting to ssDNA or shieldin disruption restores HR. Mouse genetics (knock-in mutants), immunofluorescence (RPA, RAD51 foci), epistasis analysis, END-seq Molecular cell High 31653568
2020 LC8 (DYNLL1) accumulates at laser-induced DNA damage in a 53BP1-dependent manner and requires the H2AX-MDC1-RNF8-RNF168 signal transduction cascade. Genetic inactivation of LC8 or its interaction with 53BP1 results in checkpoint defects. Loss of LC8 alleviates hypersensitivity of BRCA1-depleted cells to ionizing radiation and PARP inhibition. Laser microirradiation, Co-IP, siRNA knockdown, checkpoint assays, PARP inhibitor sensitivity Nucleic acids research Medium 30982887
2020 Protein phosphatase 5 (PP5) interacts with 53BP1 (identified by yeast two-hybrid; confirmed by Co-IP) and accelerates dephosphorylation of 53BP1 at Ser-25 and Ser-1778 following DNA damage. PP5 overexpression reduces phospho-53BP1 foci and NHEJ activity; PP5 downregulation inhibits dephosphorylation of Ser-1778 and persistence of phospho-53BP1 foci. Yeast two-hybrid, Co-IP, phosphorylation assays, NHEJ assay, immunofluorescence The Journal of biological chemistry Medium 19176521
2021 ATM phosphorylates SPOP, causing a conformational change that stabilizes SPOP interaction with 53BP1, leading to K29-linked polyubiquitination of 53BP1 and extraction from chromatin by VCP/p97 segregase. This excludes 53BP1 from DSBs during S phase to allow HR. Cancer-derived SPOP mutations block SPOP-53BP1 interaction, inducing HR defects. X-ray crystal structures of SPOP, Co-IP, ubiquitination assays, p97 interaction, siRNA/mutant analysis, immunofluorescence Science advances High 34144977
2021 AHNAK scaffolding protein binds to the 53BP1 oligomerization domain (enriched in G1) and controls 53BP1 multimerization. Loss of AHNAK causes hyper-accumulation of 53BP1 on chromatin, enhanced phase separation, and elevated p53 response. AHNAK restrains 53BP1 oligomerization to modulate p53-dependent gene activation. Co-IP, FRAP, proximity ligation assay, phase separation assays, siRNA knockdown, p53 target gene expression Molecular cell High 33961796
2021 TIRR inhibits complex formation between the 53BP1 Tudor domain and dimethylated p53 (K382me2), preventing p53 transcriptional activation. Loss of TIRR causes aberrant increase in p53 gene transactivation affecting p53-mediated cell-fate programs. Co-IP, biochemical binding assays, gene expression analysis, siRNA knockdown Molecular cell High 33961797
2021 Lamin B1 directly interacts with 53BP1 and sequesters it away from DNA damage sites under normal conditions. After DNA damage, this interaction is dissociated. Lamin B1 overexpression impedes 53BP1 recruitment to DSBs, leads to persistence of DNA damage, defective NHEJ, and increased sensitivity to DSBs. Co-IP (direct binding), immunofluorescence, domain mapping, overexpression/knockdown Science advances Medium 34452908
2021 AMPK directly phosphorylates 53BP1 at Ser1317 in response to DSBs, promoting 53BP1 recruitment to damage sites for efficient classic NHEJ. AMPK and 53BP1 interact at DSB stress conditions. In vitro kinase assay, Co-IP, immunofluorescence, NHEJ assay, phospho-site specific antibodies, CRISPR knockout Cell reports Medium 33596428
2021 NUDT16 (a TIRR homolog) regulates 53BP1 stability through its hydrolase activity by removing ADP-ribosylation from 53BP1. ADP-ribosylated 53BP1 is targeted by the PAR-binding E3 ligase RNF146 for K48-linked polyubiquitination and proteasomal degradation. DNA damage increases ADP-ribosylated 53BP1, leading to its ubiquitination and degradation. Mass spectrometry, Co-IP, in vitro de-ADP-ribosylation assay, ubiquitination assays, siRNA knockdown, immunofluorescence Cancer research Medium 31911551
2020 PRMT5 methylates and stabilizes 53BP1, promoting NHEJ repair. Src kinase phosphorylates PRMT5 at Y324 to suppress its activity by preventing S-adenosyl-L-methionine binding, thereby blocking NHEJ and promoting apoptosis after DNA damage. In vitro methylation assay, Co-IP, mass spectrometry, phosphorylation assays, NHEJ reporter assay Communications biology Medium 32759981
2022 RIF1 is a phosphopeptide-binding protein that directly interacts with three phosphorylated 53BP1 epitopes sharing an essential LxL motif followed by two closely apposed phosphorylated residues. Simultaneous mutation of these sites abolishes RIF1 accumulation at IRIF. An alternative mode of shieldin recruitment exists that still requires RIF1 but not its direct interaction with 53BP1. Peptide binding assays, mutagenesis, Co-IP, immunofluorescence (IRIF), class switch recombination assay Molecular cell High 35216668
2022 53BP1 undergoes liquid-liquid phase separation (LLPS) with HP1α at heterochromatin in a mutually dependent manner. Deletion of 53BP1 reduces heterochromatin centers and causes de-repression of heterochromatic tandem repetitive DNA. 53BP1 domains required for LLPS overlap with but are distinct from those required for DSB repair. Live-cell imaging, optoDroplet assay, domain deletion analysis, heterochromatin repeat expression analysis, CRISPR knockout Nature communications Medium 35042897
2022 In BRCA1-deficient cells, CST-Polα-primase is the major effector of shieldin-dependent DSB processing. Shieldin acts primarily by recruiting CST to DSBs; a SHLD1 mutant defective in CST binding (SHLD1Δ) is non-functional in BRCA1-deficient cells but functional at dysfunctional telomeres and CSR where CST may bind independently. CST tethering experiments, SHLD1 domain mutants, BrdU incorporation at DSBs, radial chromosome formation assay, PARP inhibitor sensitivity Nature cell biology High 35027730
2022 ZMYM2 recruitment to DSBs and suppression of 53BP1 at breaks requires the SUMO E3 ligase PIAS4 and SUMO binding by ZMYM2. Depletion of 53BP1 in ZMYM2/3-deficient cells rescues BRCA1 recruitment and HR repair, establishing that ZMYM2/3 primarily function to restrict 53BP1 to allow BRCA1-mediated HR. siRNA/CRISPR knockdown, Co-IP, immunofluorescence, HR reporter assay, PARP inhibitor sensitivity, SUMO-binding mutants Nucleic acids research Medium 35253893
2023 AlphaFold2 modeling predicted a direct interaction between the HEAT-repeat domain of RIF1 and the eIF4E-like domain of SHLD3. This was validated by in vitro pulldown and cellular assays; RIF1-SHLD3 binding is essential for shieldin recruitment to DNA damage sites, antibody class switch recombination, and PARP inhibitor sensitivity. AlphaFold2 structure prediction, in vitro pulldown, mutagenesis, cellular recruitment assay, CSR assay, PARP inhibitor sensitivity EMBO reports Medium 37306046
2023 TRABID deubiquitinase binds 53BP1 and reverses K29-linked polyubiquitination of 53BP1 mediated by SPOP, preventing 53BP1 dissociation from DSBs. Prolonged 53BP1 retention induces HR defects and chromosomal instability. TRABID overexpression in prostate cancer cells creates sensitivity to PARP inhibitors. Co-IP, ubiquitination assays (K29-linkage specific), deubiquitination assay, immunofluorescence, PARP inhibitor sensitivity Nature communications Medium 37002234
2009 PTIP, acting downstream of RNF8, controls nuclear foci formation that regulates 53BP1 localization to DNA damage sites. PTIP is required for 53BP1-dependent signaling, including ATM-mediated SMC1 phosphorylation at damage sites. PTIP functions upstream of 53BP1 and downstream of RNF8 in the DNA damage response pathway. siRNA knockdown, immunofluorescence, Co-IP, phosphorylation assays The Journal of biological chemistry Medium 19414588
2014 UbcH7 (Ube2L3) ubiquitin E2 enzyme regulates both steady-state and replicative stress-induced ubiquitination and proteasome-dependent degradation of 53BP1. N-terminal phosphorylation of 53BP1 is involved in replicative stress-induced degradation. Depletion of UbcH7 stabilizes 53BP1, inhibiting DSB end resection and increasing NHEJ. shRNA library screen, ubiquitination assays, proteasome inhibitor treatment, immunofluorescence, HR/NHEJ reporter assays Proceedings of the National Academy of Sciences of the United States of America Medium 25422456
2019 53BP1 exists as preformed dimers in the nucleoplasm that relocate to DSB sites. At DSBs, consecutive recognition of ubiquitinated H2A K15 (H2AK15ub) and dimethylated H4 K20 (H4K20me2) leads to 53BP1 oligomerization into a mature foci structure. This was demonstrated in living cells using fluorescence fluctuation spectroscopy (FFS) combined with AsiSI-inducible DSBs. Fluorescence fluctuation spectroscopy (FFS), AsiSI-inducible DSB system, live-cell nuclear architecture imaging Nature communications High 33188174
2019 H4K16 monomethylation (H4K16me1), catalyzed by histone methyltransferase GLP (G9a-like protein), promotes 53BP1 binding to damaged chromatin. H4K16me1 increases during DDR and enhances the 53BP1-H4K20me2 interaction at damaged chromatin. GLP knockdown attenuates 53BP1 foci formation and impairs NHEJ-mediated repair. Mass spectrometry (histone modification), Co-IP, ChIP, siRNA knockdown, immunofluorescence, NHEJ reporter Nucleic acids research Medium 31612207
2023 SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, reducing DNA repair at DSBs. Immunofluorescence, SARS-CoV-2 infection models (cell lines, mice, COVID-19 patients), lncRNA interference assays Nature cell biology Medium 36894671
2020 53BP1 localizes to a subset of replication forks during replication stress and is required for ATR-Chk1-p53 signaling in early S phase cells. Loss of 53BP1 leads to defective ATR-Chk1 signaling, caspase 3-mediated cell death, and degradation of nascent replicated DNA under replication stress. DNA fiber assay, immunofluorescence, siRNA/genetic knockout, ATR-Chk1 phosphorylation assays, cell death assays Molecular and cellular biology Medium 29378830
2021 ESCO2, phosphorylated by ATM at S196 and T233 in response to DNA damage, is recruited to DSB sites via MDC1 recognition of phospho-ESCO2. ESCO2-mediated acetylation of SMC3 stabilizes the cohesin complex and regulates chromatin structure at DSBs, which is essential for 53BP1 recruitment and 53BP1 microdomain formation. Co-IP, ChIP, mass spectrometry (phosphorylation sites), siRNA knockdown, immunofluorescence, in vitro acetylation assay Nucleic acids research Medium 37377435
2015 BRCA1 restricts 53BP1 phosphorylation by ATM in S and G2 phases (requiring both BRCT and RING domains of BRCA1), thereby preventing RIF1 and PTIP recruitment to DSBs in S/G2 and ensuring HR dominates. ATM-dependent 53BP1 phosphorylation is efficient only in G1. Cell synchronization, phospho-specific antibodies, siRNA knockdown, BRCA1 domain mutants, immunofluorescence Cell discovery Medium 27462418

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Double-strand break repair: 53BP1 comes into focus. Nature reviews. Molecular cell biology 874 24326623
2018 The shieldin complex mediates 53BP1-dependent DNA repair. Nature 505 30022168
2019 Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments. The EMBO journal 368 31267591
2018 53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature 356 30022158
2011 MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 336 21293379
2013 53BP1: pro choice in DNA repair. Trends in cell biology 303 24094932
2001 Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Molecular and cellular biology 300 11238909
2013 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 293 23727112
2015 53BP1 and the LINC Complex Promote Microtubule-Dependent DSB Mobility and DNA Repair. Cell 260 26544937
2018 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature 254 30046110
2014 53BP1, BRCA1, and the choice between recombination and end joining at DNA double-strand breaks. Molecular and cellular biology 244 24469398
2017 Inhibition of 53BP1 favors homology-dependent DNA repair and increases CRISPR-Cas9 genome-editing efficiency. Nature biotechnology 198 29176614
2016 53BP1 fosters fidelity of homology-directed DNA repair. Nature structural & molecular biology 185 27348077
2020 53BP1: a DSB escort. Genes & development 178 31896689
2016 53BP1 Integrates DNA Repair and p53-Dependent Cell Fate Decisions via Distinct Mechanisms. Molecular cell 150 27546791
1996 The interferon-inducible p202 protein as a modulator of transcription: inhibition of NF-kappa B, c-Fos, and c-Jun activities. Molecular and cellular biology 142 8524315
2013 Histone H4 deacetylation facilitates 53BP1 DNA damage signaling and double-strand break repair. Journal of molecular cell biology 128 23329852
2013 Role of 53BP1 in the regulation of DNA double-strand break repair pathway choice. Radiation research 121 24320053
2017 TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature 112 28241136
2009 53BP1: function and mechanisms of focal recruitment. Biochemical Society transactions 112 19614615
2018 53BP1: A key player of DNA damage response with critical functions in cancer. DNA repair 106 30497961
2017 Replication-Coupled Dilution of H4K20me2 Guides 53BP1 to Pre-replicative Chromatin. Cell reports 106 28564601
1995 Binding of an interferon-inducible protein (p202) to the retinoblastoma protein. The Journal of biological chemistry 105 7890747
2019 53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. Molecular cell 100 31653568
1996 p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition. The Journal of biological chemistry 100 8910340
2023 SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence. Nature cell biology 98 36894671
1996 Inhibition of E2F-mediated transcription by p202. The EMBO journal 95 8896460
2022 53BP1 regulates heterochromatin through liquid phase separation. Nature communications 87 35042897
2020 Roles for 53BP1 in the repair of radiation-induced DNA double strand breaks. DNA repair 86 33087281
2019 53BP1 nuclear bodies enforce replication timing at under-replicated DNA to limit heritable DNA damage. Nature cell biology 86 30804506
2013 RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks. Proceedings of the National Academy of Sciences of the United States of America 85 24324146
2011 BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability. Journal of molecular cell biology 84 21278454
2011 53BP1-mediated DNA double strand break repair: insert bad pun here. DNA repair 81 21868291
2005 ATM signaling and 53BP1. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 81 16024119
2021 Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps. Molecular cell 80 34555355
2013 Molecular mechanism for p202-mediated specific inhibition of AIM2 inflammasome activation. Cell reports 75 23850291
2018 BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance. Cell reports 70 30257212
2021 AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation. Molecular cell 69 33961796
2006 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proceedings of the National Academy of Sciences of the United States of America 66 16492765
2017 53BP1 and BRCA1 control pathway choice for stalled replication restart. eLife 65 29106372
1997 Inhibition of E2F-4/DP-1-stimulated transcription by p202. Oncogene 65 9233764
2001 The gene encoding p202, an interferon-inducible negative regulator of the p53 tumor suppressor, is a target of p53-mediated transcriptional repression. The Journal of biological chemistry 64 11013253
2015 Cell cycle-dependent inhibition of 53BP1 signaling by BRCA1. Cell discovery 63 27462418
2018 53BP1 Mediates ATR-Chk1 Signaling and Protects Replication Forks under Conditions of Replication Stress. Molecular and cellular biology 61 29378830
2020 PRMT5 promotes DNA repair through methylation of 53BP1 and is regulated by Src-mediated phosphorylation. Communications biology 57 32759981
2024 Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer. Annals of oncology : official journal of the European Society for Medical Oncology 55 38244928
2022 53BP1-shieldin-dependent DSB processing in BRCA1-deficient cells requires CST-Polα-primase fill-in synthesis. Nature cell biology 55 35027730
2020 Centrosome defects cause microcephaly by activating the 53BP1-USP28-TP53 mitotic surveillance pathway. The EMBO journal 54 33226141
2002 Interferon-inducible p202 in the susceptibility to systemic lupus. Frontiers in bioscience : a journal and virtual library 52 11991834
2021 ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication. Science advances 49 34144977
2018 Acetylation of 53BP1 dictates the DNA double strand break repair pathway. Nucleic acids research 49 29190394
2022 Multifaceted regulation and functions of 53BP1 in NHEJ‑mediated DSB repair (Review). International journal of molecular medicine 47 35583003
2021 Role of 53BP1 in end protection and DNA synthesis at DNA breaks. Genes & development 45 34503990
2018 Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR. Nature communications 44 29844495
2021 Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage. Science advances 41 34452908
2018 53BP1 can limit sister-chromatid rupture and rearrangements driven by a distinct ultrafine DNA bridging-breakage process. Nature communications 41 29445165
2018 Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. Nature structural & molecular biology 41 29967538
2009 PTIP regulates 53BP1 and SMC1 at the DNA damage sites. The Journal of biological chemistry 41 19414588
2014 UbcH7 regulates 53BP1 stability and DSB repair. Proceedings of the National Academy of Sciences of the United States of America 40 25422456
2019 LC8/DYNLL1 is a 53BP1 effector and regulates checkpoint activation. Nucleic acids research 39 30982887
2020 Spatiotemporal dynamics of 53BP1 dimer recruitment to a DNA double strand break. Nature communications 38 33188174
2020 CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks. Nature communications 38 33188175
2011 Cell type and gender-dependent differential regulation of the p202 and Aim2 proteins: implications for the regulation of innate immune responses in SLE. Molecular immunology 37 21943709
2022 RIF1 acts in DNA repair through phosphopeptide recognition of 53BP1. Molecular cell 36 35216668
2008 NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway. Cell cycle (Georgetown, Tex.) 36 19001859
1999 Reduced growth rate and transformation phenotype of the prostate cancer cells by an interferon-inducible protein, p202. Oncogene 36 9989832
2000 Tumor suppression and sensitization to tumor necrosis factor alpha-induced apoptosis by an interferon-inducible protein, p202, in breast cancer cells. Cancer research 35 10646849
2022 53BP1: Keeping It under Control, Even at a Distance from DNA Damage. Genes 34 36553657
2018 H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions. Aging 34 30312172
2020 Nudix Hydrolase NUDT16 Regulates 53BP1 Protein by Reversing 53BP1 ADP-Ribosylation. Cancer research 33 31911551
1995 Constitutive expression of the interferon-inducible protein p202 in NIH 3T3 cells affects cell cycle progression. Journal of biological regulators and homeostatic agents 33 9127631
2023 DNA damage-induced cellular senescence is regulated by 53BP1 accumulation in the nuclear foci and phase separation. Cell proliferation 32 36642815
2001 p202, an interferon-inducible protein, mediates multiple antitumor activities in human pancreatic cancer xenograft models. Cancer research 32 11585747
2013 53BP1 alters the landscape of DNA rearrangements and suppresses AID-induced B cell lymphoma. Molecular cell 31 23290917
2021 AMPK-mediated phosphorylation on 53BP1 promotes c-NHEJ. Cell reports 30 33596428
2019 GLP-catalyzed H4K16me1 promotes 53BP1 recruitment to permit DNA damage repair and cell survival. Nucleic acids research 30 31612207
2009 Protein phosphatase 5 regulates the function of 53BP1 after neocarzinostatin-induced DNA damage. The Journal of biological chemistry 30 19176521
2021 TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs. Molecular cell 28 33961797
2017 Around and beyond 53BP1 Nuclear Bodies. International journal of molecular sciences 28 29206178
2011 Aim2 deficiency in mice suppresses the expression of the inhibitory Fcgamma receptor (FcgammaRIIB) through the induction of the IFN-inducible p202, a lupus susceptibility protein. Journal of immunology (Baltimore, Md. : 1950) 28 21551362
1999 Retardation of cell proliferation after expression of p202 accompanies an increase in p21(WAF1/CIP1). Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 28 10074903
2017 Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer. Molecular cancer therapeutics 27 28958991
2019 A role of the 53BP1 protein in genome protection: structural and functional characteristics of 53BP1-dependent DNA repair. Aging 26 30996128
2023 ATM-ESCO2-SMC3 axis promotes 53BP1 recruitment in response to DNA damage and safeguards genome integrity by stabilizing cohesin complex. Nucleic acids research 25 37377435
2021 TRIM44 mediated p62 deubiquitination enhances DNA damage repair by increasing nuclear FLNA and 53BP1 expression. Oncogene 25 34211088
2020 Roles for the DNA-PK complex and 53BP1 in protecting ends from resection during DNA double-strand break repair. Journal of radiation research 25 32779701
2007 Polymorphic TP53BP1 and TP53 gene interactions associated with risk of squamous cell carcinoma of the head and neck. Clinical cancer research : an official journal of the American Association for Cancer Research 25 17634560
2001 p202, an interferon-inducible negative regulator of cell growth, is a target of the adenovirus E1A protein. Oncogene 25 11687962
2017 DNA Damage Detection by 53BP1: Relationship to Species Longevity. The journals of gerontology. Series A, Biological sciences and medical sciences 24 27573809
2015 Ectopic expression of RNF168 and 53BP1 increases mutagenic but not physiological non-homologous end joining. Nucleic acids research 24 25916843
2023 Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting. Nature communications 23 38030626
2021 Regulation of DNA double-strand break repair pathway choice: a new focus on 53BP1. Journal of Zhejiang University. Science. B 23 33448186
2012 53BP1 expression in sporadic and inherited ovarian carcinoma: Relationship to genetic status and clinical outcomes. Gynecologic oncology 23 23246380
2008 Disruption of mutually negative regulatory feedback loop between interferon-inducible p202 protein and the E2F family of transcription factors in lupus-prone mice. Journal of immunology (Baltimore, Md. : 1950) 23 18424712
2023 TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks. Nature communications 22 37002234
2022 ZMYM2 restricts 53BP1 at DNA double-strand breaks to favor BRCA1 loading and homologous recombination. Nucleic acids research 22 35253893
2018 Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double-strand breaks. eLife 22 29697047
2023 An AlphaFold2 map of the 53BP1 pathway identifies a direct SHLD3-RIF1 interaction critical for shieldin activity. EMBO reports 21 37306046
1998 p202 self-associates through a sequence conserved among the members of the 200-family proteins. FEBS letters 21 9821952
2013 Structural mechanism of DNA recognition by the p202 HINa domain: insights into the inhibition of Aim2-mediated inflammatory signalling. Acta crystallographica. Section F, Structural biology communications 20 24419611

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