PALB2 (Partner And Localizer of BRCA2; FANCN) is a nuclear scaffold/adaptor protein central to homologous recombination (HR) repair of DNA double-strand breaks and interstrand crosslinks. Its N-terminal coiled-coil binds BRCA1 and mediates self-oligomerization, while its C-terminal seven-bladed WD40 Ξ²-propeller binds BRCA2 (and also RAD51C, RAD51 and XRCC3). By simultaneously engaging BRCA1 and BRCA2, PALB2 physically bridges the two breast-cancer suppressors, forming the BRCA1-PALB2-BRCA2 complex that localizes and stabilizes BRCA2 at damaged chromatin and thereby promotes loading of the RAD51 recombinase to initiate strand invasion. PALB2 additionally binds DNA directly through an intrinsically disordered N-terminal domain (preference D-loop > dsDNA > ssDNA), stimulates RAD51-mediated D-loop formation (cooperating with RAD51AP1), possesses intrinsic strand-exchange activity, and associates with chromatin/nucleosomes via its ChAM motif. With BRCA2 it also stimulates POLH-dependent DNA synthesis at blocked replication forks. PALB2 acts in the nucleoplasm and accumulates at DNA-damage foci. Biallelic loss-of-function causes Fanconi anemia complementation group N, whereas heterozygous truncating mutations confer strong predisposition to breast, pancreatic and ovarian cancer. A secondary, HR-independent role is its interaction with KEAP1 in the oxidative-stress (NRF2) response.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005654 nucleoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PALB2 functions in the nucleoplasm, where it assembles the BRCA1-PALB2-BRCA2 HR complex. Well supported and at an appropriate level of specificity. Reason: PALB2 is a nuclear protein that acts in the nucleoplasm/on chromatin during HR; the phylogenetically-inferred location is consistent with experimental localization data. Supporting Evidence: PMID:16793542 PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. |
| GO:0000724 double-strand break repair via homologous recombination | IBA GO_REF:0000033 | ACCEPT | Summary: HR repair of DNA double-strand breaks is the central, well-established biological process for PALB2. Accept as a core function. Reason: Extensive experimental evidence establishes PALB2 as essential for HR; the IBA annotation is at the correct level of specificity. Supporting Evidence: PMID:19369211 PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. |
| GO:0003677 DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: PALB2 has genuine, experimentally demonstrated DNA-binding activity through an N-terminal DNA-binding domain, with preference D-loop > dsDNA > ssDNA. Reason: DNA binding is directly supported by in vitro EMSA experiments with purified PALB2; the phylogenetic inference is consistent with the biochemistry. Supporting Evidence: PMID:20871616 Full length PALB2 bound all three species of DNA with the following preference: D-loop > dsDNA > ssDNA |
| GO:0000724 double-strand break repair via homologous recombination | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping (IPR042417, PALB2 family) to HR repair. Consistent with the experimentally-established core function. Reason: The IEA mapping from the PALB2-specific InterPro family to HR is accurate and redundant with strong experimental evidence. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping to DNA binding, consistent with experimentally demonstrated DNA-binding activity of PALB2. Reason: Accurate electronic mapping corroborated by experimental DNA-binding data. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nucleus localization from UniProt subcellular-location mapping. Correct but less specific than nucleoplasm. Reason: PALB2 is a nuclear protein; the broad IEA location is accurate, with more specific nucleoplasm annotations also present. |
| GO:0005515 protein binding | IPI PMID:17420451 Analysis of PALB2/FANCN-associated breast cancer families. | MODIFY | Summary: IntAct interaction with BRCA2 (P51587). "Protein binding" is uninformative; the biologically meaningful activity is PALB2 acting as the molecular adaptor that bridges BRCA1 and BRCA2 for HR. Reason: Per curation guidelines the generic GO:0005515 term should be replaced with a specific molecular function. PALB2's BRCA2 interaction underlies its molecular adaptor/scaffold role coupling BRCA1 to BRCA2. Proposed replacements: protein-macromolecule adaptor activity |
| GO:0005515 protein binding | IPI PMID:19369211 PALB2 is an integral component of the BRCA complex required ... | MODIFY | Summary: Direct interaction with BRCA1 (P38398) via the coiled-coil domain; PALB2 is the molecular adaptor forming the BRCA1-PALB2-BRCA2 complex. Replace uninformative "protein binding" with protein-macromolecule adaptor activity. Reason: This is the defining BRCA1-bridging interaction of PALB2; molecular adaptor activity captures the function far better than generic protein binding. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:19369211 PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. |
| GO:0005515 protein binding | IPI PMID:19609323 Structural basis for recruitment of BRCA2 by PALB2. | MODIFY | Summary: Crystal structure of the PALB2 WD40 Ξ²-propeller bound to a BRCA2 peptide. The interaction underlies PALB2's adaptor/scaffold role recruiting BRCA2 to nuclear foci. Reason: Structurally-defined BRCA2-binding interaction; replace generic protein binding with protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:19609323 Localization of BRCA2 to nuclear foci requires its association with the partner and localizer of BRCA2 (PALB2) |
| GO:0005515 protein binding | IPI PMID:20871616 Enhancement of RAD51 recombinase activity by the tumor suppr... | MARK AS OVER ANNOTATED | Summary: IntAct interactions with RAD51 (Q06609) and RAD51AP1. PALB2 directly binds RAD51 and stimulates its recombinase (D-loop) activity; "protein binding" is uninformative and the functional role is captured in core_functions. Reason: A real, functionally important interaction, but the generic term adds no information; the meaningful activity (DNA binding and RAD51 D-loop stimulation) is annotated separately and summarized in core_functions. Supporting Evidence: PMID:20871616 PALB2 binds DNA and physically interacts with RAD51. |
| GO:0005515 protein binding | IPI PMID:22193777 ChAM, a novel motif that mediates PALB2 intrinsic chromatin ... | MARK AS OVER ANNOTATED | Summary: Interactions detected in the ChAM/chromatin-binding study (with BRCA1, BRCA2 and RAD51 co-complex members). Uninformative generic term. Reason: These co-complex interactions reflect the BRCA complex/chromatin association already captured by more specific annotations; protein binding itself is uninformative. |
| GO:0005515 protein binding | IPI PMID:22244764 Structural basis for molecular interactions involving MRG do... | MARK AS OVER ANNOTATED | Summary: Structural study of MRG domains; interaction with MORF4L1/MRG15 (Q9UBU8-2). Peripheral chromatin-targeting interaction annotated with an uninformative term. Reason: MORF4L1 binding relates to chromatin targeting, a secondary/supporting role; protein binding is uninformative as a molecular function. |
| GO:0005515 protein binding | IPI PMID:22293751 APRIN is a cell cycle specific BRCA2-interacting protein req... | MARK AS OVER ANNOTATED | Summary: Interaction with BRCA2 (P51587) detected in a study of the BRCA2-interacting protein APRIN/PDS5B. Incidental co-complex detection; uninformative term. Reason: The BRCA2 co-complex detection here is incidental to the paper's focus; the informative PALB2-BRCA2 adaptor function is captured elsewhere. |
| GO:0005515 protein binding | IPI PMID:24141787 Breast cancer-associated missense mutants of the PALB2 WD40 ... | MARK AS OVER ANNOTATED | Summary: The PALB2 WD40 domain directly binds RAD51C, RAD51, BRCA2 and XRCC3, scaffolding an HR complex. Real, mechanistically important interactions but annotated with an uninformative term. Reason: The scaffolding role is captured by protein-macromolecule adaptor activity in core_functions; the generic protein binding term adds no information. Supporting Evidence: PMID:24141787 the PALB2 WD40 domain may scaffold the RAD51C, RAD51, and BRCA2 HR proteins into a complex |
| GO:0005515 protein binding | IPI PMID:24485656 Breast cancer proteins PALB2 and BRCA2 stimulate polymerase ... | MARK AS OVER ANNOTATED | Summary: Direct interaction with DNA polymerase eta (POLH, Q9Y253); with BRCA2, PALB2 stimulates POLH-mediated DNA synthesis at blocked forks. Uninformative generic term. Reason: A genuine but specialized replication-associated role; protein binding is uninformative and the function is described in core_functions/notes. Supporting Evidence: PMID:24485656 PALB2 and BRCA2 interact with PolΞ· and are required to sustain the recruitment of PolΞ· at blocked replication forks. |
| GO:0005515 protein binding | IPI PMID:25960410 Structural Basis for Multi-specificity of MRG Domains. | MARK AS OVER ANNOTATED | Summary: Structural study of MRG domain multi-specificity; interaction with MORF4L1/MRG15 (Q9UBU8-2). Peripheral chromatin-targeting interaction with uninformative term. Reason: Same as other MORF4L1 interactions; protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:28319063 Compromised BRCA1-PALB2 interaction is associated with breas... | MODIFY | Summary: Direct interaction with BRCA1 (P38398) via the coiled-coil; the L35P variant abrogates it, linking loss of the PALB2-BRCA1 bridge to breast-cancer risk. Reason: Defining BRCA1-bridging interaction; replace generic protein binding with protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:28319063 The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome (protein communities/disease networks); interaction with MORF4L1 (Q9UBU8-2). Uninformative generic term from a large-scale screen. Reason: Large-scale interactome hit; protein binding is uninformative as a molecular function. |
| GO:0005515 protein binding | IPI PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | MARK AS OVER ANNOTATED | Summary: DNA-repair network analysis; interaction with BRCA1 (P38398). Uninformative generic term from a network study. Reason: The functionally meaningful BRCA1 bridge is already captured by MODIFY of the dedicated BRCA1-interaction rows; this network-derived generic annotation is uninformative. |
| GO:0005515 protein binding | IPI PMID:30410870 Two Missense Variants Detected in Breast Cancer Probands Pre... | MODIFY | Summary: Interaction with BRCA2 (P51587); the paper characterizes BRCA2 missense variants that prevent BRCA2-PALB2 binding. Supports the adaptor/scaffold role. Reason: BRCA2-binding interaction central to the PALB2 adaptor function; replace generic protein binding with protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Binary interactome (HuRI) interaction with KEAP1 (Q14145). Reflects PALB2's secondary role in the KEAP1-NRF2 oxidative-stress pathway, not its HR-scaffold core function. Reason: A real but HR-independent interaction annotated with an uninformative term; not a core molecular function of PALB2. The mechanistic basis of this secondary role is established by PMID:22331464 (KEAP1-NRF2 antioxidant response). Supporting Evidence: PMID:22331464 PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: BioPlex proteome-scale network; interactions include BRCA2 (P51587), RAD51 (Q06609) and KEAP1 (Q14145). Large-scale generic interaction annotation. Reason: High-throughput interactome data; protein binding is uninformative and the meaningful interactions are captured elsewhere. |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | MARK AS OVER ANNOTATED | Summary: Breast-cancer protein interaction landscape; interactions include BRCA2 (P51587) and KEAP1 (Q14145). Large-scale generic interaction annotation. Reason: High-throughput interactome data; protein binding is uninformative. |
| GO:0000724 double-strand break repair via homologous recombination | IDA PMID:28398198 Functional and mutational landscapes of BRCA1 for homology-d... | ACCEPT | Summary: ComplexPortal IDA for HR; the study shows the BRCA1-PALB2 interaction governs the choice between HR and single-strand annealing. Core function. Reason: Direct assay evidence for PALB2's role in HR-mediated repair. Supporting Evidence: PMID:28398198 the BRCA1-PALB2 interaction dictates the choice between HR and SSA |
| GO:0005634 nucleus | NAS PMID:19369211 PALB2 is an integral component of the BRCA complex required ... | ACCEPT | Summary: Nuclear localization (ComplexPortal NAS). Correct; PALB2 acts in the nucleus, accumulating with RAD51 at DNA-damage sites. Reason: Consistent with all experimental localization data for PALB2. Supporting Evidence: PMID:19369211 the focal concentration of PALB2 and RAD51 at DSBs |
| GO:1990391 DNA repair complex | IPI PMID:19369211 PALB2 is an integral component of the BRCA complex required ... | ACCEPT | Summary: PALB2 is part of the BRCA1-PALB2-BRCA2 DNA repair complex. Appropriately specific complex annotation. Reason: Directly supported; PALB2 is an integral component of the trimeric BRCA1-PALB2-BRCA2 HR complex. Supporting Evidence: PMID:19369211 serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence localizes PALB2 to the nucleoplasm. Consistent with its site of action. Reason: Direct immunofluorescence evidence for nucleoplasmic localization, the site where PALB2 assembles the HR complex. |
| GO:0016607 nuclear speck | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence also reports nuclear-speckle localization. Retained but not part of the core HR function, which occurs at damage foci/chromatin. Reason: A valid IDA localization, but nuclear speckles are not where PALB2's core HR scaffold activity is established; mark as non-core rather than removing. |
| GO:0003697 single-stranded DNA binding | IMP PMID:31017574 Novel RNA and DNA strand exchange activity of the PALB2 DNA ... | ACCEPT | Summary: PALB2 N-terminal DNA-binding domain binds ssDNA and supports strand exchange; mutating the DNA-binding site reduces RAD51 foci and halves HDR efficiency. Reason: Experimentally demonstrated ssDNA binding that is functionally required for efficient HDR. Supporting Evidence: PMID:31017574 We identified a major DNA-binding site of PALB2, mutations in which reduce RAD51 foci formation and the overall HDR efficiency in cells by 50%. |
| GO:0003677 DNA binding | EXP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr... | ACCEPT | Summary: The PALB2 DNA-binding domain binds DNA and supports strand exchange in vitro. Genuine molecular function. Reason: Direct experimental demonstration of DNA binding by the PALB2-DBD. Supporting Evidence: PMID:39584160 the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro |
| GO:0042803 protein homodimerization activity | EXP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr... | ACCEPT | Summary: PALB2 self-associates via a coiled-coil-mediated dimerization, stabilized by its intrinsically disordered regions. Experimentally demonstrated. Reason: Direct biophysical evidence for coiled-coil-mediated homodimerization, a property important for focal accumulation at DNA breaks. Supporting Evidence: PMID:39584160 Coiled-coil mediated dimerization is stabilized by interaction between intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction. |
| GO:0042803 protein homodimerization activity | IMP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr... | ACCEPT | Summary: Mutational evidence supporting PALB2 self-association/dimerization. Consistent with the EXP annotation from the same study. Reason: Corroborates the homodimerization activity; retained for consistency with the EXP annotation. Supporting Evidence: PMID:39584160 Coiled-coil mediated dimerization is stabilized by interaction between intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction. |
| GO:0003697 single-stranded DNA binding | EXP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr... | ACCEPT | Summary: ssDNA binding by the PALB2-DBD, which also drives its structural compaction and tetramerization. Consistent with the IMP ssDNA-binding annotation. Reason: Direct experimental evidence for ssDNA binding by PALB2. Supporting Evidence: PMID:39584160 Single-stranded (ss)DNA binding promotes additional structural compaction and protein tetramerization. |
| GO:0051289 protein homotetramerization | EXP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr... | KEEP AS NON CORE | Summary: ssDNA binding promotes PALB2 tetramerization in vitro, proposed to underlie a strand-exchange mechanism. Genuine but specialized higher-order self-assembly. Reason: Experimentally supported oligomeric state, but a mechanistic detail of PALB2 self-assembly rather than a core molecular function on its own; retained as non-core. Supporting Evidence: PMID:39584160 Single-stranded (ss)DNA binding promotes additional structural compaction and protein tetramerization. |
| GO:0003677 DNA binding | IPI PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr... | ACCEPT | Summary: DNA binding annotated via interaction with a DNA substrate (ChEBI:9160). Consistent with the other DNA-binding annotations for PALB2. Reason: Corroborates PALB2 DNA binding; retained for consistency with the EXP/IDA/IBA DNA-binding annotations. Supporting Evidence: PMID:39584160 the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro |
| GO:0005634 nucleus | EXP PMID:16793542 Control of BRCA2 cellular and clinical functions by a nuclea... | ACCEPT | Summary: Experimental nuclear localization from the founding PALB2 study. Correct. Reason: Direct experimental evidence of nuclear localization. Supporting Evidence: PMID:16793542 PALB2 colocalizes with BRCA2 in nuclear foci |
| GO:0005634 nucleus | EXP PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo... | ACCEPT | Summary: Experimental nuclear localization within the XPG-BRCA2-PALB2 HR complex study. Correct. Reason: Direct experimental localization evidence; PALB2 is chromatin-associated and forms damage-induced foci. Supporting Evidence: PMID:26833090 XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation |
| GO:0005634 nucleus | EXP PMID:28319063 Compromised BRCA1-PALB2 interaction is associated with breas... | ACCEPT | Summary: Experimental nuclear localization consistent with PALB2 focus formation at DNA damage sites. Correct. Reason: Direct experimental localization evidence; PALB2 forms ionizing radiation-induced nuclear foci. Supporting Evidence: PMID:28319063 wt PALB2 forms IRIF that largely co-localize with those of BRCA1 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9704408 | ACCEPT | Summary: Reactome-asserted nucleoplasm location (HR pathway module). Consistent with PALB2's site of action. Reason: Correct location; PALB2 acts in the nucleoplasm during HR. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9704330 | ACCEPT | Summary: Reactome-asserted nucleoplasm location (defective HR module). Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005515 protein binding | IPI PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo... | MARK AS OVER ANNOTATED | Summary: Interactions within the ERCC5/XPG-BRCA2-PALB2-DSS1-RAD51 HR complex (withs include XPG, BRCA2, RAD51). Real complex membership, uninformative generic term. Reason: The specific complex membership is captured by the protein-containing-complex annotation from the same paper; protein binding itself is uninformative. Supporting Evidence: PMID:26833090 XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. |
| GO:0032991 protein-containing complex | IDA PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo... | MODIFY | Summary: PALB2 is a component of an HR complex (ERCC5/XPG, BRCA2, PALB2, DSS1, RAD51). "Protein-containing complex" is very generic; a DNA repair complex term is more informative. Reason: Replace the top-level generic complex term with the more specific DNA repair complex, matching the HR complex demonstrated here and the BRCA1-PALB2-BRCA2 complex. Proposed replacements: DNA repair complex Supporting Evidence: PMID:26833090 XPG directly interacts with BRCA2, RAD51, and PALB2 |
| GO:0000724 double-strand break repair via homologous recombination | IMP PMID:26323318 NUCKS1 is a novel RAD51AP1 paralog important for homologous ... | ACCEPT | Summary: HR annotation from a study (NUCKS1/RAD51AP1) that used PALB2 depletion within its HR (gene-conversion) assays. HR is the well-established core process for PALB2. Reason: HR is unambiguously PALB2's core function; per guidelines an experimental annotation is not removed for lack of cached full text, and the assigned process is clearly correct and directly assayed here. Supporting Evidence: PMID:26323318 knockdown of PALB2 by one of two different siRNAs elicits a more dramatic effect on gene conversion frequency than depletion of either NUCKS1 or RAD51AP1 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685838 | ACCEPT | Summary: Reactome nucleoplasm location (HR/D-loop pathway). Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686410 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686440 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686469 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686483 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693539 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693584 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693589 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693593 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693620 | ACCEPT | Summary: Reactome nucleoplasm location for the "D-loop formation mediated by PALB2, BRCA2 and RAD51" reaction. Directly relevant and consistent. Reason: Correct nucleoplasmic location; this reaction is a canonical PALB2 HR step. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9701199 | ACCEPT | Summary: Reactome nucleoplasm location (defective D-loop formation module). Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9709601 | ACCEPT | Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9853389 | ACCEPT | Summary: Reactome nucleoplasm location (FIGNL1 binds RAD51 module). Consistent. Reason: Correct nucleoplasmic location. |
| GO:0000724 double-strand break repair via homologous recombination | IDA PMID:19369211 PALB2 is an integral component of the BRCA complex required ... | ACCEPT | Summary: Direct assay evidence that disrupting the BRCA1-PALB2 interaction causes defective HR. Core function. Reason: Direct experimental support for PALB2's essential role in HR repair. Supporting Evidence: PMID:19369211 cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair |
| GO:0000724 double-strand break repair via homologous recombination | IDA PMID:19423707 PALB2 regulates recombinational repair through chromatin ass... | ACCEPT | Summary: PALB2 chromatin association and oligomerization are required to anchor the BRCA2Β·RAD51 machinery at breaks for HR. Core function. Reason: Direct experimental evidence linking PALB2 focal accumulation to proficient HR. Supporting Evidence: PMID:19423707 PALB2 exists as homo-oligomers and that PALB2 oligomerization is essential for its focal accumulation at DNA breaks in vivo |
| GO:0003677 DNA binding | IDA PMID:20871616 Enhancement of RAD51 recombinase activity by the tumor suppr... | ACCEPT | Summary: Purified PALB2 binds ssDNA, dsDNA and D-loop (preference D-loop > dsDNA > ssDNA) via its N-terminal half. Direct biochemical evidence. Reason: Direct in vitro demonstration of PALB2 DNA-binding activity. Supporting Evidence: PMID:20871616 Full length PALB2 bound all three species of DNA with the following preference: D-loop > dsDNA > ssDNA |
| GO:0005515 protein binding | IPI PMID:19423707 PALB2 regulates recombinational repair through chromatin ass... | MODIFY | Summary: Interaction with BRCA2 (P51587); PALB2 refines its BRCA2-binding motif to the WD40 repeats and its chromatin association is a prerequisite for BRCA2 loading. Part of the adaptor/scaffold function. Reason: BRCA2-binding interaction central to PALB2's adaptor role; replace generic protein binding with protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:19423707 PALB2 localizes to chromatin and assembled as oligomers at the site of DNA damage, which then serves as an anchor for the loading of BRCA2 and RAD51 |
| GO:0005515 protein binding | IPI PMID:20332121 MRG15 binds directly to PALB2 and stimulates homology-direct... | MARK AS OVER ANNOTATED | Summary: Direct interaction with MORF4L1/MRG15 (chromodomain protein), which promotes chromatin-associated homology-directed repair. Peripheral chromatin-targeting interaction with an uninformative term. Reason: A genuine chromatin-targeting interaction, but a supporting rather than core role; protein binding is uninformative as a molecular function. Supporting Evidence: PMID:20332121 PALB2 binds directly to a conserved chromodomain protein, MRG15 |
| GO:0031491 nucleosome binding | IDA PMID:22193777 ChAM, a novel motif that mediates PALB2 intrinsic chromatin ... | NEW | Summary: PALB2's chromatin-association motif (ChAM) directly and intrinsically binds nucleosomes, mediating constitutive chromatin association that is distinct from the N-terminal DNA-binding regions. ChAM deletion reduces PALB2 and RAD51 accumulation at DNA-damage sites and confers mitomycin C hypersensitivity. Reason: A genuine, experimentally demonstrated molecular function (direct nucleosome binding by the ChAM motif) that is absent from GOA and was previously reflected only as uninformative "protein binding" (PMID:22193777 row above). Added as a NEW annotation but kept non-core: ChAM-mediated nucleosome/chromatin association is a targeting/anchoring activity that helps retain and position the BRCA1-PALB2-BRCA2 complex on chromatin, rather than the central molecular-adaptor function itself. Supporting Evidence: PMID:22193777 ChAM robustly binds to nucleosomes PMID:22193777 chromatin-association motif (ChAM), an evolutionarily conserved motif in PALB2, is necessary and sufficient to mediate its chromatin association in both unperturbed and damaged cells |
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Download this section (compressed HTML)Q: Beyond its scaffold role, how much of PALB2's direct DNA binding and intrinsic strand-exchange activity contributes to HR in vivo versus in vitro?
Q: What is the physiological significance of the KEAP1-PALB2 interaction relative to PALB2's dominant HR-scaffold function?
Experiment: Generate separation-of-function PALB2 alleles that selectively disrupt DNA binding versus BRCA1 or BRCA2 binding, and assay HR efficiency, RAD51 foci formation, and PARP-inhibitor sensitivity to dissect the DNA-binding contribution from the adaptor/scaffold contribution.
Experiment: Structural and biophysical characterization (cryo-EM/SAXS) of the full BRCA1-PALB2-BRCA2 assembly on damaged chromatin to define the stoichiometry and geometry of the adaptor bridge.
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