Affinage

CRB2

Protein crumbs homolog 2 · UniProt Q5IJ48

Length
1285 aa
Mass
134.3 kDa
Annotated
2026-06-09
66 papers in source corpus 33 papers cited in narrative 33 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

The CRB2 timeline describes two coherent but distinct protein contexts that share the gene symbol: the fission yeast DNA damage checkpoint mediator Crb2 (a 53BP1-related ortholog) and the mammalian Crumbs-family transmembrane polarity protein CRB2. In S. pombe, Crb2 is a checkpoint adaptor that operates in a Cut5(TopBP1)–Crb2–Chk1 sensor-transmitter pathway, acting upstream of Chk1 to enforce DNA damage-induced arrest (PMID:9407031). Crb2 is recruited to double-strand breaks through cooperative reading of two histone marks: its tandem Tudor domain binds H4-K20me2 (deposited by Set9/Kmt5), specifically discriminating the dimethyl over trimethyl state, and its BRCT2 domain binds γ-H2A phosphorylated by Rad3/Tel1, with the two modules contributing additively to focus formation and checkpoint signaling (PMID:15550243, PMID:15226425, PMID:17190600, PMID:18826944, PMID:20679485, PMID:20679488). A parallel CDK-dependent pathway, requiring Cdc2 phosphorylation of Crb2-T215 and association with Cut5, can recruit Crb2 to breaks independently of the histone-reading route (PMID:16778077). Crb2 function further requires BRCT-mediated homo-oligomerization (PMID:15229228, PMID:18676809), and once positioned it recruits and activates Chk1 via Rad3-phosphorylated SQ/TQ motifs that directly bind Chk1 (PMID:14739927, PMID:22792081). Cdc2 phosphorylation of T215 governs the temporal switch between checkpoint maintenance and recovery, controlling re-entry into the cycle after repair and channeling checkpoint output (PMID:10488332, PMID:16314498, PMID:24861625), and Crb2 also restrains long-range DSB resection to balance repair pathway choice (PMID:12023299, PMID:29697047). In mammals, CRB2 is an apicolateral/subapical membrane polarity protein required for epiblast polarity during gastrulation (PMID:22072575), retinal lamination and suppression of late-born progenitor proliferation through regulation of Notch and YAP/Hippo targets (PMID:23001562, PMID:24339791), and for development and maintenance of polarized retinal pigment epithelium (PMID:26404741, PMID:34262913). In kidney podocytes, recessive CRB2 mutations cause steroid-resistant nephrotic syndrome, and CRB2 is required for foot process arborization, slit diaphragm formation, nephrin trafficking, actin cytoskeleton organization, and podocyte survival, with its loss activating YAP mechanosignaling (PMID:25557779, PMID:34654837, PMID:40062402). CRB2 surface delivery depends on PDIA3-mediated disulfide bridge formation, and disease variants are retained in the ER (PMID:36549870); its extracellular domain mediates homo- and heterodimerization with CRB1 (PMID:38570189).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Established Crb2 as a checkpoint mediator acting upstream of Chk1, answering how DNA damage signals are transmitted to cell cycle arrest in fission yeast.

    Evidence Two-hybrid interaction, genetic suppressor analysis, and phosphorylation/checkpoint arrest assays placing Crb2 in a Cut5-Crb2-Chk1 pathway

    PMID:9407031

    Open questions at the time
    • Did not define the molecular basis of Crb2 recruitment to damage
    • Direct vs indirect Chk1 activation not resolved
  2. 1999 High

    Identified CDK phosphorylation of Crb2-T215 as the switch enabling checkpoint recovery, distinguishing checkpoint maintenance from termination.

    Evidence In vitro Cdc2 kinase assay, T215A mutagenesis, and checkpoint re-entry assays

    PMID:10488332

    Open questions at the time
    • Mechanism by which T215 phosphorylation silences Chk1 not defined
    • Whether T215 also affects recruitment unaddressed at this stage
  3. 2002 Medium

    Linked Crb2 to recombinational repair downstream of Cdc2, showing the checkpoint protein also regulates the repair machinery (Top3) in G2.

    Evidence Genetic epistasis, IR survival, and Rhp51 focus analysis

    PMID:12023299

    Open questions at the time
    • Direct biochemical link between Crb2 and Top3 not shown
    • Single-lab genetic inference
  4. 2003 High

    Demonstrated Crb2 forms DSB-localized nuclear foci and separated initial recruitment from Rad1/Rad3/Rad17-dependent retention.

    Evidence Live-cell fluorescence microscopy, co-localization with Rad22, deletion analysis

    PMID:12917337

    Open questions at the time
    • Molecular determinants of initial recruitment not yet identified
    • Retention mechanism via 9-1-1 not mechanistically defined
  5. 2004 High

    Defined the histone-mark code for Crb2 recruitment by identifying Set9/H4-K20 methylation and γ-H2A as the marks read at breaks, and showed BRCT-mediated oligomerization is the essential BRCT function.

    Evidence Genetic epistasis, ChIP, histone mutagenesis, Crb2 focus imaging, domain-swap rescue, and co-IP/in vitro Chk1 assays across four studies

    PMID:14739927 PMID:15226425 PMID:15229228 PMID:15550243

    Open questions at the time
    • Structural basis of mark recognition not yet solved
    • Methylation-state specificity not resolved
  6. 2006 High

    Solved the structural basis of dimethyl-state-specific H4-K20me2 reading by the tandem Tudor domain and showed histone-reading and CDK/Cut5 pathways are parallel recruitment routes.

    Evidence X-ray crystallography, NMR, in vitro binding, and HO-induced DSB genetic epistasis

    PMID:16778077 PMID:17190600

    Open questions at the time
    • Relative contribution of each pathway to checkpoint output in vivo not quantified
  7. 2008 High

    Provided the structural and mutational basis for cooperative bivalent recruitment, showing BRCT2 dimerization and γ-H2A phosphopeptide binding have separable roles in checkpoint versus repair.

    Evidence Crystal structure of BRCT2-phospho-H2A complex, mutagenesis, binding and focus/checkpoint assays

    PMID:18676809 PMID:18826944

    Open questions at the time
    • How dimerization couples to downstream Chk1 activation not fully resolved
  8. 2010 High

    Established that Tudor (H4K20me2) and BRCT (γ-H2A) modules contribute additively to recruitment, defining the bivalent-anchoring logic of Crb2.

    Evidence Precise mutagenesis of binding residues (S548, K619), double-mutant epistasis, focus imaging, and checkpoint kinase assays

    PMID:20679485 PMID:20679488

    Open questions at the time
    • Stoichiometry of dual-mark engagement at a single break unknown
  9. 2012 High

    Resolved how Crb2 activates Chk1, showing Rad3-phosphorylated SQ/TQ motifs directly recruit Chk1 and can bypass upstream 9-1-1 when tethered.

    Evidence Phosphopeptide binding, mutagenesis, fusion-protein tethering rescue, and co-IP

    PMID:22792081

    Open questions at the time
    • Conformational change in Chk1 upon binding not defined
  10. 2010 High

    Extended CRB2 biology to mammals by showing human CRB2 inhibits γ-secretase cleavage of APP via its transmembrane domain.

    Evidence Knockdown/overexpression in HEK293 and SH-SY5Y, cell-free γ-secretase assay, co-IP, domain deletion

    PMID:20299451

    Open questions at the time
    • Physiological relevance in brain not established
    • Relationship to CRB2 polarity function unclear
  11. 2014 Medium

    Identified CRB2 as a developmental polarity protein essential in early embryo, retina, and kidney, with mutations causing human steroid-resistant nephrotic syndrome.

    Evidence Mouse germline and conditional knockouts, zebrafish loss-of-function and complementation, human exome sequencing, and nephrin trafficking analysis (spanning 2011–2014)

    PMID:22072575 PMID:23001562 PMID:24493795 PMID:25557779

    Open questions at the time
    • Direct molecular link between CRB2 and nephrin trafficking not defined
    • How CRB2 controls progenitor proliferation mechanistically unresolved
  12. 2021 Medium

    Defined CRB2 cytoskeletal and survival functions in podocytes and RPE, linking its loss to actin disorganization, apoptosis, and epithelial polarity failure.

    Evidence Podocyte- and RPE-specific knockouts, human cell knockdown, F-actin quantification, apoptosis assays, and polarity protein imaging

    PMID:24339791 PMID:34262913 PMID:34654837

    Open questions at the time
    • Direct effector linking CRB2 to actin not identified
    • Single-lab signaling inferences
  13. 2022 Medium

    Established post-translational control of CRB2 trafficking, showing PDIA3-mediated disulfide bridge formation is required for ER-to-surface transport and that disease variants are ER-retained, and that the extracellular domain mediates CRB1-CRB2 dimerization.

    Evidence Live-cell imaging of CRB2-GFP, PDIA3 knockout, disease-variant analysis, autoantibody immunization model, and reciprocal co-IP with CRB1/CRB3 (2022–2024)

    PMID:35985815 PMID:36549870 PMID:38570189

    Open questions at the time
    • Functional consequence of CRB1-CRB2 heterodimers in vivo not defined
    • Autoantibody mechanism vs genetic loss not fully reconciled
  14. 2025 Medium

    Connected CRB2 loss to YAP mechanotransduction and, separately, identified a nuclear CRB2 role in H4K20me2-mediated transcriptional repression of SLC7A11 controlling ferroptosis.

    Evidence siRNA knockdown with YAP reporters and ERISM contractility measurement; CRB2 over/knockdown with ChIP for H4K20me2, LSD1-USP7 co-IP, and ferroptosis assays (2025–2026)

    PMID:40062402 PMID:40991301

    Open questions at the time
    • How a membrane polarity protein influences nuclear H4K20me2 mechanistically unclear
    • Single-lab findings, awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether and how the chromatin-reading checkpoint functions of yeast Crb2 mechanistically relate to the membrane-polarity functions of mammalian CRB2, and how CRB2 transduces polarity loss into YAP, actin, and transcriptional outcomes.
  • No unified molecular model across the two contexts
  • Effectors linking CRB2 surface signaling to nuclear/cytoskeletal outputs not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 3 R-HSA-73894 DNA Repair 3 R-HSA-162582 Signal Transduction 2
Partners
CHK1CRB1CUT5PDIA3RAD3

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Fission yeast Crb2 (S. pombe ortholog) physically interacts with Cut5 (TopBP1 homolog) and Chk1 in two-hybrid assays; Crb2 is required for checkpoint arrests induced by irradiation and polymerase mutations; upon UV damage Crb2 is transiently phosphorylated upstream of Chk1; moderate overexpression of Chk1 suppresses crb2 mutant phenotypes, placing Crb2 upstream of Chk1 in a Cut5-Crb2-Chk1 checkpoint sensor-transmitter pathway. Two-hybrid interaction assay, genetic epistasis (suppressor analysis), phosphorylation analysis by gel mobility shift, checkpoint arrest assays Genes & development High 9407031
1999 Cdc2 kinase directly phosphorylates Crb2 at threonine-215 in vitro; this phosphorylation is required for cells to re-enter the cell cycle after DNA damage-induced checkpoint arrest; a non-phosphorylatable T215A mutant remains arrested even after DNA repair and maintains phosphorylated Chk1. In vitro kinase assay with purified Cdc2; site-directed mutagenesis (T215A); checkpoint re-entry assays Molecular cell High 10488332
2002 In fission yeast, Cdc2-cyclin B kinase activity influences recombinational repair at two stages: early Rhp51 focus formation (redundant with Rad50) and late topoisomerase III (Top3) regulation; the effect on Top3 function is mediated through the BRCT-domain checkpoint protein Crb2, directly linking checkpoint proteins to recombinational repair in G2. Genetic epistasis, ionizing radiation survival assays, Rhp51 focus analysis by fluorescence microscopy Genes & development Medium 12023299
2003 Crb2 localizes to distinct nuclear foci at sites of DNA double-strand breaks (DSBs) in live fission yeast cells; Crb2 co-localizes with Rad22 at persistent foci; damage-induced Crb2 foci still form in cells lacking Rad1, Rad3, and Rad17, but do not persist, indicating that Rad1/Rad3 complexes are required for retention but not initial recruitment of Crb2 at DSBs. Live-cell fluorescence microscopy, co-localization analysis, genetic deletion analysis Molecular and cellular biology High 12917337
2004 The SET domain protein Set9 is responsible for H4-K20 methylation in S. pombe; genetic experiments link Set9 to Crb2; Set9 is required for Crb2 localization to sites of DNA damage; loss of Set9 or mutation of H4-K20 impairs cell survival after genotoxic challenge and compromises checkpoint-mediated cell cycle arrest. Genetic epistasis, ChIP, fluorescence microscopy of Crb2 foci, checkpoint survival assays Cell High 15550243
2004 Crb2 regulates DNA damage checkpoint through temporal and dynamic interactions with Rad3, Chk1, and replication factor Cut5; active complex formation between Chk1 and Crb2 is regulated by Rad3 and is maximal during checkpoint arrest; Chk1 activation requires two steps involving loss of Rad3-Chk1 and Rad3-Crb2 interactions and subsequent association of hyperphosphorylated Chk1 with Crb2; an in vitro Chk1 assay demonstrates activation requires Crb2 BRCT domain; direct Rad3-Crb2 interaction is inhibitory to Rad3 activity. Co-immunoprecipitation, in vitro Chk1 kinase assay, two-hybrid interaction, genetic analysis The EMBO journal High 14739927
2004 Crb2 undergoes homo-oligomerization through its tandem BRCT domains; truncated Crb2 lacking BRCT domains is defective in DNA damage checkpoint signaling, but addition of heterologous dimerization motifs largely restores function; replacement of BRCT domains with a dimerization motif also rescues cells from the dominant-negative effect of overexpressed BRCT domains, demonstrating that the essential function of tandem BRCT domains is to oligomerize Crb2. Domain truncation and replacement, dimerization motif substitution, checkpoint signaling assays The Journal of biological chemistry High 15229228
2004 Gamma-H2A (phosphorylated histone H2A at the SQE motif by Rad3/Tel1 ATR/ATM-related kinases) is required for large-scale recruitment of Crb2 to damaged DNA and for proper checkpoint phosphorylation of Crb2 and Chk1; H2A-AQE mutations cause defective Crb2 phosphorylation and failure to recruit Crb2 to DSBs; H2A-AQE mutations partially suppress IR hypersensitivity of crb2Δ cells in a mechanism requiring Rqh1 helicase. Site-directed mutagenesis of histone H2A, fluorescence microscopy of Crb2 foci, checkpoint phosphorylation assays, genetic epistasis Molecular and cellular biology High 15226425
2005 Cooperative control of Crb2 by ATM-family kinases and Cdc2 is essential for the DNA damage checkpoint; crb2-T215A cells can initiate but not sustain a checkpoint response; gamma-H2A is essential for checkpoint function specifically in crb2-T215A cells; inactivation of Cdc2 in gamma-H2A-defective cells impairs Crb2-dependent Chk1 signaling, demonstrating that full Crb2 activity requires Cdc2-mediated phosphorylation of T215. Genetic epistasis, checkpoint kinase assays, site-directed mutagenesis Molecular and cellular biology High 16314498
2005 Crb2 mediates Chk1 activation in fission yeast; Crb2 BRCT domain mutants that experience damaged replication forks activate a Chk1 pathway that induces sustained spindle checkpoint activation in a Mad2-dependent fashion, delaying metaphase-to-anaphase transition. BRCT domain mutant analysis, checkpoint assays, Mad2 genetic epistasis Molecular and cellular biology Medium 16107732
2006 Using X-ray crystallography and NMR, both 53BP1 and fission yeast Crb2 contain tandem tudor domains that directly bind histone H4 specifically dimethylated at Lys20 (H4-K20me2); a unique five-residue binding cage in 53BP1 is structurally conserved in Crb2 and accommodates dimethyllysine but excludes trimethyllysine, establishing the molecular basis of methylation state-specific recognition. X-ray crystallography, NMR spectroscopy, in vitro binding assays Cell High 17190600
2006 Crb2 IRIF formation requires two histone modifications (H2A C-terminal phosphorylation and H4-K20 methylation) that cooperate in the same recruitment pathway and require Crb2's Tudor and BRCT motifs; an alternative, parallel recruitment pathway sufficient for checkpoint activation requires a CDK phosphorylation site (T215) in Crb2 that mediates association with Cut5 (TopBP1 homolog); Cut5 also accumulates at HO-induced DSBs. Fluorescence microscopy of Crb2 foci, genetic epistasis with histone modification mutants, HO endonuclease-induced DSB assay, domain mutation analysis Genes & development High 16778077
2008 Crystal structure of Crb2-BRCT2 domain alone and in complex with a phosphorylated H2A.1 peptide reveals the structural basis for Crb2 dimerization and direct interaction with gamma-H2A.1 at IRIF; mutational analysis shows that dimerization mutants are genotoxin-sensitive and defective in checkpoint signaling and Chk1 phosphorylation, while phosphopeptide-binding mutants are only slightly IR-sensitive, have extended checkpoint delays, and form IRIF but show reduced Rpa1 and Rad22 foci indicating a DNA repair defect. X-ray crystallography, site-directed mutagenesis, in vitro binding, checkpoint phosphorylation assays, fluorescence microscopy of foci Genes & development High 18676809
2008 The tandem tudor domains of Crb2 preferentially bind di-methylated H4K20 over other methylation states; disruption of the tudor-binding motif or loss of Set9/Kmt5 (the H4K20 methylating enzyme) ablates Crb2 localization to DSBs and impairs checkpoint function; dimethylation but not trimethylation of H4K20 is specifically required for Crb2 localization, checkpoint function, and cell survival after DNA damage. In vitro tudor binding assays with differentially methylated peptides, fluorescence microscopy, checkpoint function assays, genetic knockout The Journal of biological chemistry High 18826944
2010 Crb2 BRCT2 domain residues serine-548 and lysine-619 make polar interactions with the phosphate group of phospho-H2A (gamma-H2A); mutations of these residues critically impair Crb2 IRIF formation and checkpoint function with additive effects when combined; combining either mutation with the T215A CDK phosphorylation site mutation completely abrogates Crb2 IRIF and function, demonstrating cooperative phosphate interactions between BRCT2 and gamma-H2A coupled with Tudor domain interactions with H4-K20me2. Site-directed mutagenesis, fluorescence microscopy, checkpoint kinase assays, double-mutant epistasis Molecular and cellular biology High 20679485
2010 Loss of Crb2 BRCT domain phospho-H2AX binding activity severely impairs Crb2 accumulation at IR-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest; combined ablation of both tudor (H4K20me2-binding) and BRCT (pH2AX-binding) modules yields a strikingly additive reduction in Crb2 activity. BRCT domain mutagenesis, fluorescence microscopy, checkpoint arrest assays, double-mutant analysis Molecular and cellular biology High 20679488
2010 Human CRB2 (the most abundant Crumbs ortholog in the brain) inhibits gamma-secretase cleavage of APP to reduce Abeta and AICD production; CRB2 knockdown increases gamma-secretase cleavage products; CRB2 interacts with the gamma-secretase complex but is not a competitive substrate; the transmembrane domain of CRB2 is indispensable for Abeta inhibition and mediates binding to the gamma-secretase complex; co-overexpression of presenilin-1 or APH-1 abrogates inhibition. Transfection/knockdown in HEK293 and SH-SY5Y cells, cell-free gamma-secretase assay, co-immunoprecipitation, domain deletion analysis The Journal of biological chemistry High 20299451
2011 Germline knockout of mouse Crb2 causes embryonic lethality by E12.5; the primary defect is disturbed epiblast cell polarity at the primitive streak affecting epithelial-to-mesenchymal transition (EMT) during gastrulation, resulting in impaired mesoderm and endoderm formation, demonstrating an essential role for CRB2 in early embryonic epithelial polarity. Gene targeting/knockout, histological and developmental analysis of embryos Developmental dynamics Medium 22072575
2012 Phosphorylation-dependent interactions between Crb2 and Chk1 are essential for the DNA damage checkpoint; Crb2 recruits Chk1 to DSBs through direct physical interaction; a pair of conserved SQ/TQ motifs in Crb2 (Rad3 phosphorylation consensus) is required for Chk1 recruitment and activation; tethering Crb2 and Chk1 together rescues the SQ/TQ mutation; a 19-amino-acid phosphorylated peptide containing these motifs is sufficient for Chk1 binding in vitro; tethering this peptide to DSBs via Rad22/Rad52 or Rad4/Cut5 fusion can rescue crb2Δ checkpoint defect and even bypass the need for the 9-1-1 complex. In vitro binding with phosphopeptides, site-directed mutagenesis, fusion protein tethering, checkpoint assays, co-immunoprecipitation PLoS genetics High 22792081
2012 Conditional knockout of CRB2 in the developing mouse retina causes progressive disorganization, thinning of the photoreceptor layer, disruption of adherens junctions, increased numbers of late-born rod photoreceptors and Müller glia with concomitant programmed cell death, demonstrating an essential role for CRB2 in retinal lamination and suppression of late-born progenitor proliferation. Conditional gene knockout, confocal scanning laser ophthalmoscopy, OCT, electroretinography, histology Human molecular genetics Medium 23001562
2013 Combined ablation of Crb1 and Crb2 in retinal progenitor cells causes severe retinal dysfunction and dysregulation of Notch1 and YAP/Hippo signaling pathway target genes and increased P120-catenin levels; CRB1 and CRB2 restrain proliferation of retinal progenitor cells and control cell cycle distribution. Conditional double knockout, gene expression profiling, cell cycle analysis, electroretinography PLoS genetics Medium 24339791
2014 Recessive mutations in human CRB2 cause steroid-resistant nephrotic syndrome; zebrafish crb2b loss-of-function mutation shows that crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking; complementation experiments in zebrafish confirm that human CRB2 mutations result in loss of function. Homozygosity mapping, whole exome sequencing, zebrafish loss-of-function mutant analysis, complementation assay, nephrin trafficking analysis American journal of human genetics High 25557779
2014 Targeted ablation of CRB2 specifically in photoreceptors causes progressive photoreceptor degeneration (RP-like phenotype) with early abnormal lamination onset; ablation in Müller cells causes late-onset retinal disorganization; short-term loss of CRB2 in adult photoreceptors but not in Müller glial cells causes sporadic loss of adhesion between photoreceptors and Müller cells. Cell-type specific conditional deletion, AAV-Cre and shRNA-mediated ablation, OCT, electroretinography, histology Human molecular genetics Medium 24493795
2014 Hyperactive Cdc2 (cdc2.1w) mutation causes cells to bypass Chk1 and enter extended cell-cycle arrest dependent on Cds1 kinase in the presence of broken replication forks; this Chk1 bypass requires the mitotic Cdc2 phosphorylation site Crb2-T215, suggesting that presence of the T215 phosphorylation channels Rad3 activity towards Cds1 instead of Chk1; hyperactive Cdc2 locks cells in a G1-like repair mode favoring NHEJ over recombination. Genetic analysis with cdc2.1w mutant, checkpoint kinase assays, recombination assays Nucleic acids research Medium 24861625
2015 CRB2 protein is expressed in mouse retinal pigment epithelium (RPE) and is restricted to the apicolateral membrane, specifically at tight junctions; CRB2 completes a fully expressed Crumbs complex in the RPE apico-lateral membrane together with other CRB complex components. Custom antibody generation, confocal immunofluorescence microscopy, subcellular fractionation Scientific reports Medium 26404741
2018 The 53BP1 ortholog Crb2 and Rev7 specifically repress long-range resection of DSBs through the RecQ helicase-dependent pathway, thereby preventing hyper-resection; this is established using a single-cell microscopy assay for resection phases in live S. pombe cells. Live-cell single-cell microscopy resection assay, genetic deletion, pathway dissection eLife Medium 29697047
2021 Knockdown of CRB2 in human RPE cells disrupts tight junction maintenance, affects cell cycle arrest, and in vivo knockdown of CRB2 in mouse RPE perturbs distribution of apical polarity proteins and results in invasion of activated microglial cells into the subretinal space, demonstrating CRB2 is required for development and maintenance of polarized RPE epithelium. siRNA knockdown, in vitro polarization assay, AAV-mediated in vivo knockdown, immunofluorescence Frontiers in cell and developmental biology Medium 34262913
2021 Podocyte-specific Crb2 knockout mice develop massive albuminuria and focal segmental glomerulosclerosis; human podocytes lacking CRB2 show significantly decreased F-actin positive area and increased susceptibility to apoptosis, demonstrating that CRB2 is required for proper actin cytoskeleton organization and podocyte survival. Podocyte-specific conditional knockout, electron microscopy, siRNA knockdown in human podocytes, F-actin quantification, apoptosis assay Scientific reports High 34654837
2022 CRB2 protein transport from the ER to the plasma membrane requires proper formation of disulfide bridges; disease-associated CRB2 missense variants and variants with mutated putative disulfide bridge-forming cysteines accumulate predominantly at the ER rather than reaching the plasma membrane; CRB2 is retained at the ER in cells lacking protein disulfide isomerase A3 (PDIA3), identifying post-translational disulfide bridge formation as a crucial step for CRB2 surface transport. Live-cell imaging of CRB2-GFP fusion proteins, BFP-labeled plasma membrane reporter, PDIA3 knockout cells, in silico variant selection Life science alliance High 36549870
2022 Anti-Crb2 autoantibodies cause nephrotic syndrome in mice; immunization with the recombinant extracellular domain of Crb2 generates autoantibodies that colocalize with Crb2 at podocyte foot processes; anti-Crb2 antibody treatment of podocytes increases phosphorylation of ezrin (which connects Crb2 to the cytoskeleton), alters Crb2 localization, and disturbs actin distribution. Mouse immunization model, anti-Crb2 antibody incubation of podocyte cell line, phosphorylation assays, immunofluorescence colocalization Journal of the American Society of Nephrology Medium 35985815
2024 Human CRB1 and CRB2 co-localize in the human retina and iPSC-derived retinal organoids; retina-specific pull-downs show CRB1 is enriched in CRB2 samples; co-immunoprecipitation demonstrates human canonical CRB1 interacts with CRB1 and CRB2 but not with CRB3 (which lacks an extracellular domain), indicating the extracellular domain mediates CRB1-CRB2 homo- and heterodimerization. Co-immunoprecipitation, retina-specific pull-down, co-localization in human retina and retinal organoids Life science alliance Medium 38570189
2025 CRB2 knockdown in podocytes induces YAP transcriptional activity and target gene expression, upregulates YAP-mediated mechanosignaling, and increases density of focal adhesions and F-actin; using ERISM, CRB2 knockdown enhances podocyte contractility in a substrate stiffness-dependent manner with impaired mechanosensing at low substrate stiffness, demonstrating CRB2 regulates podocyte mechanotransduction via YAP signaling. siRNA knockdown, YAP reporter assays, elastic resonator interference stress microscopy (ERISM), F-actin quantification, YAP inhibitor treatment American journal of physiology. Renal physiology Medium 40062402
2026 CRB2 inhibits transcription of the ferroptosis suppressor SLC7A11 by increasing dimethylation of histone H4 lysine 20 (H4K20me2) at its promoter; mechanistically, CRB2 hinders the interaction between the LSD1(E8A) histone lysine demethylase isoform and the deubiquitinase USP7, facilitating LSD1(E8A) degradation and thereby increasing H4K20me2 levels; this epigenetic axis sensitizes HNSCC cells to ferroptosis. CRB2 overexpression/knockdown, ferroptosis assays (erastin/RSL3), ChIP for H4K20me2, co-immunoprecipitation of LSD1-USP7 interaction, protein stability assays Cancer research Medium 40991301

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 802 17190600
2004 Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell 442 15550243
1997 Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1. Genes & development 223 9407031
2004 Histone H2A phosphorylation controls Crb2 recruitment at DNA breaks, maintains checkpoint arrest, and influences DNA repair in fission yeast. Molecular and cellular biology 159 15226425
2002 Cdc2-cyclin B kinase activity links Crb2 and Rqh1-topoisomerase III. Genes & development 140 12023299
2006 Histone modification-dependent and -independent pathways for recruitment of checkpoint protein Crb2 to double-strand breaks. Genes & development 128 16778077
2014 Defects of CRB2 cause steroid-resistant nephrotic syndrome. American journal of human genetics 87 25557779
2003 Retention but not recruitment of Crb2 at double-strand breaks requires Rad1 and Rad3 complexes. Molecular and cellular biology 85 12917337
2005 Characterization of the Crumbs homolog 2 (CRB2) gene and analysis of its role in retinitis pigmentosa and Leber congenital amaurosis. Molecular vision 79 15851977
2019 Human iPSC-Derived Retinas Recapitulate the Fetal CRB1 CRB2 Complex Formation and Demonstrate that Photoreceptors and Müller Glia Are Targets of AAV5. Stem cell reports 78 30956116
2012 Loss of CRB2 in the mouse retina mimics human retinitis pigmentosa due to mutations in the CRB1 gene. Human molecular genetics 73 23001562
1999 Cdc2 phosphorylation of Crb2 is required for reestablishing cell cycle progression after the damage checkpoint. Molecular cell 73 10488332
2013 Targeted ablation of CRB1 and CRB2 in retinal progenitor cells mimics Leber congenital amaurosis. PLoS genetics 64 24339791
2011 Deficiency in Crumbs homolog 2 (Crb2) affects gastrulation and results in embryonic lethality in mice. Developmental dynamics : an official publication of the American Association of Anatomists 64 22072575
2008 Structural and functional analysis of the Crb2-BRCT2 domain reveals distinct roles in checkpoint signaling and DNA damage repair. Genes & development 57 18676809
2008 Di-methyl H4 lysine 20 targets the checkpoint protein Crb2 to sites of DNA damage. The Journal of biological chemistry 56 18826944
2004 Regulation of checkpoint kinases through dynamic interaction with Crb2. The EMBO journal 48 14739927
2014 CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice. Human molecular genetics 46 24565864
2014 Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa. Human molecular genetics 40 24493795
2016 Expansion of phenotype and genotypic data in CRB2-related syndrome. European journal of human genetics : EJHG 39 27004616
2019 Loss of CRB2 in Müller glial cells modifies a CRB1-associated retinitis pigmentosa phenotype into a Leber congenital amaurosis phenotype. Human molecular genetics 34 30239717
2013 Microarray and morphological analysis of early postnatal CRB2 mutant retinas on a pure C57BL/6J genetic background. PloS one 34 24324803
2005 The fission yeast Crb2/Chk1 pathway coordinates the DNA damage and spindle checkpoint in response to replication stress induced by topoisomerase I inhibitor. Molecular and cellular biology 31 16107732
2018 CRB2 mutation causes autosomal recessive retinitis pigmentosa. Experimental eye research 28 30593785
2004 Homo-oligomerization is the essential function of the tandem BRCT domains in the checkpoint protein Crb2. The Journal of biological chemistry 28 15229228
2018 CRB2 in immature photoreceptors determines the superior-inferior symmetry of the developing retina to maintain retinal structure and function. Human molecular genetics 25 29893966
2010 Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein by binding to the presenilin complex. The Journal of biological chemistry 24 20299451
2010 BRCT domain interactions with phospho-histone H2A target Crb2 to chromatin at double-strand breaks and maintain the DNA damage checkpoint. Molecular and cellular biology 23 20679485
2020 AAV-CRB2 protects against vision loss in an inducible CRB1 retinitis pigmentosa mouse model. Molecular therapy. Methods & clinical development 22 33575434
2018 Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double-strand breaks. eLife 22 29697047
2016 Expanding the phenotype of CRB2 mutations - A new ciliopathy syndrome? Clinical genetics 22 26925547
2005 Cooperative control of Crb2 by ATM family and Cdc2 kinases is essential for the DNA damage checkpoint in fission yeast. Molecular and cellular biology 22 16314498
2022 A Novel Mouse Model of Idiopathic Nephrotic Syndrome Induced by Immunization with the Podocyte Protein Crb2. Journal of the American Society of Nephrology : JASN 18 35985815
2021 Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis. Scientific reports 18 34654837
2012 Phosphorylation-dependent interactions between Crb2 and Chk1 are essential for DNA damage checkpoint. PLoS genetics 18 22792081
2016 Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome. Pediatric nephrology (Berlin, Germany) 17 27942854
2015 CRB2 completes a fully expressed Crumbs complex in the Retinal Pigment Epithelium. Scientific reports 16 26404741
2019 CRB2 Loss in Rod Photoreceptors Is Associated with Progressive Loss of Retinal Contrast Sensitivity. International journal of molecular sciences 15 31438467
2010 Requirement for the phospho-H2AX binding module of Crb2 in double-strand break targeting and checkpoint activation. Molecular and cellular biology 15 20679488
2023 Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla. Acta neuropathologica communications 14 36803301
2022 CRB2 enhances malignancy of glioblastoma via activation of the NF-κB pathway. Experimental cell research 12 35219647
2022 Six new cases of CRB2-related syndrome and a review of clinical findings in 28 reported patients. Clinical genetics 12 36071576
1999 The S/M checkpoint at 37 degrees C and the recovery of viability of the mutant poldeltats3 require the crb2+/rhp9+ gene in fission yeast. Molecular & general genetics : MGG 12 9928931
2021 Key Role for CRB2 in the Maintenance of Apicobasal Polarity in Retinal Pigment Epithelial Cells. Frontiers in cell and developmental biology 11 34262913
2019 Targeted deletion of Crb1/Crb2 in the optic vesicle models key features of leber congenital amaurosis 8. Developmental biology 11 31145883
2023 Characterization and AAV-mediated CRB gene augmentation in human-derived CRB1KO and CRB1KOCRB2+/- retinal organoids. Molecular therapy. Methods & clinical development 10 37886604
2018 Expression and localization of the polarity protein CRB2 in adult mouse brain: a comparison with the CRB1rd8 mutant mouse model. Scientific reports 10 30076417
2003 High dosage Rhp51 suppression of the MMS sensitivity of DNA structure checkpoint mutants reveals a relationship between Crb2 and Rhp51. Genes to cells : devoted to molecular & cellular mechanisms 9 12839619
2024 Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina. Life science alliance 8 38570189
2007 Overexpression of human CRB1 or related isoforms, CRB2 and CRB3, does not regulate the human presenilin complex in culture cells. Biochemistry 8 17988153
2023 Novel variants in CRB2 targeting the malfunction of slit diaphragm related to focal segmental glomerulosclerosis. Pediatric nephrology (Berlin, Germany) 6 37452832
2022 Loss of surface transport is a main cellular pathomechanism of CRB2 variants causing podocytopathies. Life science alliance 6 36549870
2018 A case report of CRB2 mutation identified in a Chinese boy with focal segmental glomerulosclerosis. Medicine 5 30212996
2014 Hyperactive Cdc2 kinase interferes with the response to broken replication forks by trapping S.pombe Crb2 in its mitotic T215 phosphorylated state. Nucleic acids research 5 24861625
2025 CRB2 depletion induces YAP signaling and disrupts mechanosensing in podocytes. American journal of physiology. Renal physiology 3 40062402
2022 Exome Sequencing Revealed a Novel Splice Site Variant in the CRB2 Gene Underlying Nephrotic Syndrome. Medicina (Kaunas, Lithuania) 3 36556986
2003 Expression, purification and preliminary X-ray analysis of the BRCT domain from Rhp9/Crb2. Acta crystallographica. Section D, Biological crystallography 2 12832769
2026 CRB2 Activates an Epigenetic Axis to Promote Ferroptosis in Head and Neck Squamous Cell Carcinoma. Cancer research 0 40991301
2026 CRB2 Facilitates Epithelial Ovarian Cancer Progression by Inducing Polarity Changes via Activation of the Wnt/PCP Signalling Pathway. Journal of cellular and molecular medicine 0 41906249
2026 A Novel CRB2 Mutation Associated With FSGS and ESRD in an Adult Patient. Case reports in nephrology 0 42169774
2025 CRISPR/Cas9-mediated generation of a homozygous CRB2 knockout H1 human embryonic stem cell line. Stem cell research 0 39987590
2025 Expanded CRB2-related disease phenotype: multisystem involvement and post-transplant complications in monozygotic twins. Pediatric nephrology (Berlin, Germany) 0 40456931
2025 CRB2-Related Syndrome in 2 New Patients: Three Novel Variants. Molecular syndromology 0 40734719
2025 Heterozygous variants of uncertain significance in NPHS1 and CRB2 in a newborn with congenital nephrotic syndrome of the Finnish type and multiple fetal anomalies: a case report. AME case reports 0 40761226
2024 CRB2 Depletion Induces YAP Signaling and Disrupts Mechanosensing in Podocytes. bioRxiv : the preprint server for biology 0 39484460
2024 Biochemical characterization and structure prediction of the Cerrado soil CRB2(1) metagenomic dioxygenase. Enzyme and microbial technology 0 39527864

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