Affinage

PALB2

Partner and localizer of BRCA2 · UniProt Q86YC2

Length
1186 aa
Mass
131.3 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 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

PALB2 (Partner and Localizer of BRCA2) is the central scaffold of homologous recombination (HR) repair of DNA double-strand breaks, physically bridging BRCA1 and BRCA2 so that the recombinase machinery can be assembled at sites of damage (PMID:19268590, PMID:19584259). Through its N-terminal coiled-coil it binds BRCA1 (residues L21/L24/L35) and through its C-terminus it binds BRCA2, thereby relaying BRCA1-mediated recruitment to BRCA2-RAD51 organization and strand invasion (PMID:17287723, PMID:19584259); structurally the coiled-coil forms an antiparallel leucine-zipper that exists as a homodimer or as a BRCA1 heterodimer, and the switch from PALB2 homodimer to PALB2-BRCA1 heterodimer acts as the regulatory gate that activates HR (PMID:22941656, PMID:30289697). PALB2 recruitment to breaks proceeds through an ubiquitin signaling cascade (MDC1, RNF8, RAP80, Abraxas upstream of BRCA1, and RNF168-generated ubiquitylated H2A read by BARD1-BRCA1), with the BRCA1-PALB2 heterodimer rather than the homodimer mediating RAD51 loading (PMID:23038782, PMID:28240985, PMID:34408138). PALB2 carries intrinsic chromatin- and DNA-binding activities: a chromatin-association motif (ChAM) that engages the nucleosome acidic patch—an interaction antagonized by 53BP1 in BRCA1-deficient cells—and an N-terminal DNA-binding domain that stimulates RAD51 and possesses RAD51-independent strand-exchange activity (PMID:22193777, PMID:31017574, PMID:32041954). Steady-state localization to actively transcribed genes occurs via MRG15 recognition of SETD2-deposited H3K36me3, protecting these regions during replication, and PALB2 is additionally recruited to stalled forks by phosphorylated RPA and sustains DNA polymerase η-dependent synthesis at blocked forks (PMID:28673974, PMID:25113031, PMID:24485656). ATM/ATR-dependent phosphorylation of N-terminal S/Q sites is required for proper RAD51 foci formation and HR, and PALB2 also contributes to the G2/M checkpoint independently of CHK1/CHK2 (PMID:27113759, PMID:26420486, PMID:30337689). Beyond DNA repair, PALB2 binds KEAP1 through a shared ETGE motif to promote NRF2-mediated antioxidant responses (PMID:22331464). Patient-derived and systematic variant analyses establish that disruption of the BRCA1-PALB2 or BRCA2-PALB2 interactions, or destabilization of the WD40 domain, abolishes HR and confers sensitivity to platinum and PARP inhibitors, and mouse models disrupting these interactions produce Fanconi anemia-like and tumor-prone phenotypes (PMID:28319063, PMID:25016020, PMID:32732220, PMID:31636395, PMID:31757951).

Mechanistic history

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

    Established PALB2 as a direct, functionally essential partner of BRCA2, defining its founding role in HR and crosslink repair.

    Evidence Co-IP, HR and crosslink repair assays, and a truncating frameshift mutant lacking BRCA2 binding

    PMID:17287723

    Open questions at the time
    • Did not define how PALB2 itself is recruited to damage sites
    • No structural basis of the BRCA2 interaction
  2. 2009 High

    Placed PALB2 as the physical link bridging BRCA1 and BRCA2, mapping independent N-terminal (BRCA1) and C-terminal (BRCA2) interaction interfaces and ordering the recruitment hierarchy.

    Evidence Co-IP, siRNA, foci, HR assays in PALB2-deficient cells, and pulldown with point/deletion mutants (L21P, L24P)

    PMID:19268590 PMID:19584259

    Open questions at the time
    • Upstream signal recruiting BRCA1-PALB2 not defined
    • No atomic structure of the coiled-coil interface
  3. 2010 High

    Linked PALB2 to chromatin context by identifying MRG15 as a direct partner that loads the BRCA complex onto chromatin and suppresses aberrant recombination.

    Evidence Purified complex analysis, Co-IP, interface mutagenesis, HR/SCE/gene-conversion assays, chromatin fractionation

    PMID:19553677 PMID:20332121

    Open questions at the time
    • Histone mark recognized by MRG15 in this context not yet defined
    • Mechanism of recombination suppression unresolved
  4. 2012 High

    Defined the autonomous chromatin- and self-association properties of PALB2, revealing a homodimer-to-BRCA1-heterodimer switch and a dedicated chromatin-association motif controlling damage-site accumulation.

    Evidence Self-association and DNA-binding assays, RAD51 filament assay, ChAM deletion mutants, chromatin fractionation, MMC sensitivity

    PMID:22193777 PMID:22941656

    Open questions at the time
    • Trigger converting homodimer to heterodimer not molecularly defined
    • Chromatin receptor for ChAM not yet identified in these studies
  5. 2012 High

    Showed PALB2 also binds the oxidative-stress sensor KEAP1 via a NRF2-like ETGE motif, extending PALB2 function into redox homeostasis beyond DNA repair.

    Evidence Co-IP, ETGE-motif competition binding assay, ROS measurement, NRF2 reporter, nuclear fractionation

    PMID:22331464

    Open questions at the time
    • Whether redox role intersects with HR function is unresolved
    • In vivo significance not established here
  6. 2012 High

    Ordered the ubiquitin-dependent recruitment pathway directing PALB2 to breaks, demonstrating that PALB2 localization (not BRCA1 binding per se) is the rate-limiting requirement for HR.

    Evidence PALB2-BRCT fusion epistasis, RAD51/HR/MMC assays, siRNA of MDC1/RNF8/RAP80/Abraxas

    PMID:23038782

    Open questions at the time
    • Direct ubiquitin reader not yet identified at this stage
    • Did not resolve fork-associated recruitment
  7. 2014 High

    Extended PALB2 function to stalled replication forks, showing recruitment via phosphorylated RPA and support of Polη-dependent synthesis at blocked forks.

    Evidence Fiber analysis, foci, cell-free RPA-ssDNA recruitment, phospho-defective RPA2 mutants, in vitro D-loop synthesis, Co-IP

    PMID:24485656 PMID:25113031

    Open questions at the time
    • Coordination between RPA- and BRCA1-dependent recruitment unclear
    • Relative contribution to fork protection vs DSB repair not parsed
  8. 2016 High

    Defined ATM/ATR phosphorylation of N-terminal S/Q sites as a post-translational switch required for RAD51 foci and HR, separable from the PALB2 checkpoint function.

    Evidence Phosphosite mapping by MS, phospho-deficient/mimic mutants, ATM/BRCA1 dependency, RAD51/HDR/checkpoint assays

    PMID:26420486 PMID:27113759

    Open questions at the time
    • Downstream effector reading PALB2 phosphorylation unknown
    • How phosphorylation gates dimer switching not defined
  9. 2017 High

    Identified RNF168 as a direct WD40-domain partner coupling PALB2 HR assembly to H2A ubiquitylation, and tied steady-state PALB2 chromatin residency to the SETD2/H3K36me3/MRG15 axis protecting active genes.

    Evidence Co-IP, domain mapping, HR/foci assays, ChIP-seq, MRG15-interface mutants, camptothecin sensitivity, DNA fiber analysis

    PMID:28240985 PMID:28673974

    Open questions at the time
    • Interplay between transcription-coupled residency and damage recruitment unresolved
    • Generality across cell types not established
  10. 2017 High

    Linked specific germline coiled-coil variants (e.g. L35P) abrogating BRCA1-PALB2 binding to loss of HR and to clinical drug sensitivity, connecting interaction integrity to tumor suppression.

    Evidence Co-IP, HR assay, platinum/PARP sensitivity, tumor exome sequencing with HRD signature, segregation analysis

    PMID:28319063

    Open questions at the time
    • Variant-specific quantitative HR thresholds for cancer risk not defined
  11. 2018 High

    Solved the atomic structure of the PALB2 coiled-coil and demonstrated separable BRCA1 vs BRCA2 contributions to the G2/M checkpoint, defining the molecular and functional architecture of the dimer switch.

    Evidence Solution NMR, AUC, mutagenesis, clonogenic survival, flow-cytometry checkpoint assays with interaction mutants

    PMID:30289697 PMID:30337689

    Open questions at the time
    • Full-length PALB2 structure unresolved
    • Mechanism of checkpoint maintenance by PALB2-BRCA2 not detailed
  12. 2019 High

    Established PALB2 as an intrinsic DNA-binding recombination enzyme with RAD51-independent strand-exchange activity, and systematically mapped damaging VUS to coiled-coil (BRCA1 binding) and WD40 (stability/localization) defects.

    Evidence In vitro DNA binding and strand exchange with purified protein, RAD51/HDR assays, systematic VUS analysis in Palb2-KO mES cells, Co-IP, stability and localization assays

    PMID:31017574 PMID:31636395 PMID:31757951

    Open questions at the time
    • In vivo relevance of strand-exchange and RNA-substrate activity unclear
    • Physiological substrate of inverse strand exchange unknown
  13. 2020 High

    Revealed competition between PALB2 ChAM and 53BP1 for the nucleosome acidic patch, explaining how 53BP1 loss restores HR in BRCA1-deficient cells, and confirmed FA-like phenotypes from disrupting the Brca1-Palb2 interface in vivo.

    Evidence BRCA1-null/53BP1-depleted models, ChAM/acidic-patch binding assays, RAD51/HR assays; Brca1 L1363P knock-in mouse phenotyping

    PMID:32041954 PMID:32732220

    Open questions at the time
    • Regulation of the ChAM/53BP1 competition under normal BRCA1 status not defined
  14. 2021 High

    Mapped the upstream ubiquitin-reading cascade in vivo (RNF168-mUb-H2A-BARD1-BRCA1-PALB2) and uncovered a PALB2-RAD52 complex acting in sdRNA-directed repair at transcriptional pause sites.

    Evidence Mouse Brca1CC × Rnf168 epistasis, foci, Co-IP, domain mapping; sdRNA characterization and PALB2-RAD52 functional analysis

    PMID:33536619 PMID:34408138

    Open questions at the time
    • PALB2-RAD52 mechanism is from a single study
    • Relationship of sdRNA pathway to canonical BRCA2-RAD51 HR unresolved
  15. 2022 Medium

    Demonstrated druggability of PALB2 protein-protein interactions and downstream immune consequences, showing WD40-targeting compounds disrupt PALB2-BRCA2 and that interaction loss activates cGAS-STING signaling.

    Evidence Structure-based screening, NanoBiT PPI/docking/binding assays, clonogenic and xenograft assays (PGG); mouse BRCA1-PALB2 disruption with cGAS-STING/PD-L1 readouts in HCC; prostate cancer PARP-inhibitor sensitivity

    PMID:35006619 PMID:35768576 PMID:35926819

    Open questions at the time
    • Inhibitor specificity and therapeutic window not established
    • cGAS-STING immune effects shown in a single tumor model

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how PALB2's distinct molecular activities—dimer-switch gating, intrinsic strand exchange, transcription-coupled chromatin residency, fork protection, and KEAP1/NRF2 signaling—are temporally and spatially integrated within a single regulatory program.
  • No full-length structural model integrating the domains
  • Hierarchy and timing among recruitment routes (RNF168/BRCA1, RPA, ChAM, MRG15) not unified
  • In vivo significance of non-HR functions (NRF2, RAD52/sdRNA) versus canonical HR unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 2 GO:0042393 histone binding 2 GO:0003723 RNA binding 1 GO:0098772 molecular function regulator activity 1 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-1640170 Cell Cycle 2 R-HSA-4839726 Chromatin organization 2 R-HSA-69306 DNA Replication 2 R-HSA-74160 Gene expression (Transcription) 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
BRCA1BRCA2KEAP1MRG15RAD51CRAD52RNF168USP22
Complex memberships
BRCA1-PALB2-BRCA2 HR complexPALB2-MRG15 complexPALB2-RAD52 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 PALB2 directly interacts with BRCA2 and this interaction is crucial for BRCA2 DNA damage response functions and tumor suppression activity. A truncated PALB2 protein caused by the c.1592delT frameshift mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Co-immunoprecipitation, homologous recombination assay, crosslink repair assay, BRCA2-binding capacity assay Nature High 17287723
2009 PALB2 physically links BRCA1 and BRCA2 in the DNA-damage response. BRCA1 associates with BRCA2 through PALB2; this interaction is abrogated in PALB2-deficient cells. BRCA1 promotes concentration of PALB2 and BRCA2 at DNA-damage sites, and the BRCA1-PALB2 interaction is required for homologous recombination repair. Co-immunoprecipitation, siRNA knockdown, immunofluorescence foci analysis, homologous recombination assay in PALB2-deficient Fanconi anemia cells Current biology : CB High 19268590
2009 PALB2 independently interacts with BRCA1 through its N-terminus (via coiled-coil domain residues L21 and L24) and with BRCA2 through its C-terminus. PALB2 mediates the physical interaction of BRCA2 with a C-terminal fragment of BRCA1. BRCA1 recruits PALB2, which in turn organizes BRCA2 and RAD51. Both PALB2-BRCA1 and PALB2-BRCA2 interactions are required for resistance to mitomycin C and homologous recombination repair of DNA double-strand breaks. Pulldown with bacterially expressed protein fragments, Co-immunoprecipitation from cell extracts, reconstitution in PALB2-deficient cells with point mutants (L21P, L24P) and deletion mutants, RAD51/BRCA foci assembly assay, mitomycin C resistance assay, HR repair assay Molecular cancer research : MCR High 19584259
2010 PALB2 binds directly to MRG15, a chromodomain protein component of histone acetyltransferase-deacetylase complexes. MRG15 interacts with the entire BRCA complex (BRCA1, PALB2, BRCA2, RAD51). MRG15 deficiency, like PALB2 or BRCA2 deficiency, reduces homology-directed DNA repair efficiency and causes hypersensitivity to DNA interstrand crosslinking agents. Knockdown of MRG15 diminishes recruitment of PALB2, BRCA2, and RAD51 to DNA damage sites and reduces chromatin loading of PALB2 and BRCA2. Purified protein complex analysis, Co-immunoprecipitation, siRNA knockdown, HR assay, mitomycin C sensitivity assay, immunofluorescence foci analysis, chromatin fractionation Journal of cell science High 19553677 20332121
2009 MRG15 directly interacts with PALB2 through an evolutionarily conserved region. Loss of the PALB2-MRG15 interaction does not impair RAD51 foci formation or mitomycin C sensitivity but leads to hyper-recombination, specifically increased gene conversion rates and elevated sister chromatid exchange frequencies, suggesting MRG15 suppresses aberrant recombination via PALB2. Co-immunoprecipitation, site-directed mutagenesis of PALB2-MRG15 interface, gene conversion assay, sister chromatid exchange assay, RAD51 foci analysis The Journal of biological chemistry High 19553677
2012 PALB2 interacts directly with KEAP1, an oxidative stress sensor that normally binds and represses the NRF2 transcription factor. PALB2 shares a conserved ETGE-type KEAP1-binding motif with NRF2 and competes with NRF2 for KEAP1 binding. PALB2 promotes NRF2 nuclear accumulation and function, lowers cellular reactive oxygen species levels, and regulates the rate of NRF2 nuclear export following oxidative induction. Co-immunoprecipitation, direct binding assay with ETGE-motif competition, ROS measurement, NRF2 reporter assay, nuclear fractionation Molecular and cellular biology High 22331464
2012 The N-terminal coiled-coil motif of PALB2 mediates its self-association (homodimerization), and monomeric PALB2 shows higher efficiency to bind DNA and promote RAD51 filament formation. Overexpression of the PALB2 coiled-coil domain severely affects RAD51 loading at DNA damage sites by competing with the PALB2-BRCA1 interaction. Upon DNA damage, a switch from PALB2-PALB2 homodimerization to PALB2-BRCA1 interaction activates homologous recombination. Biochemical self-association assay, DNA binding assay, RAD51 filament formation assay, immunofluorescence foci analysis, overexpression competition experiment Nucleic acids research High 22941656
2012 The chromatin-association motif (ChAM), an evolutionarily conserved region of PALB2, is necessary and sufficient to mediate intrinsic chromatin binding of PALB2 in both unperturbed and damaged cells. ChAM is distinct from previously described DNA-binding regions. Deletion of ChAM decreases PALB2 and RAD51 accumulation at DNA damage sites and confers cellular hypersensitivity to mitomycin C. Chromatin fractionation, deletion mutagenesis, immunofluorescence foci analysis, mitomycin C sensitivity assay EMBO reports High 22193777
2012 MDC1 and RNF8 function upstream of BRCA1 in a pathway that directs BRCA1-dependent localization of PALB2 to DNA double-strand breaks. Bypassing BRCA1 by fusing PALB2 to BRCA1 BRCT repeats restores RAD51 foci formation and HR repair in PALB2-deficient cells even when PALB2 cannot bind BRCA1, demonstrating the critical role of PALB2 localization. The BRCA1-PALB2 heterodimer (not the PALB2-PALB2 homodimer) mediates these HR responses. PALB2 localization requires MDC1, RNF8, RAP80, and Abraxas upstream of BRCA1. PALB2-BRCT fusion protein epistasis experiment, PALB2-deficient cell reconstitution, RAD51 foci assay, HR repair assay, mitomycin C resistance assay, siRNA depletion of MDC1/RNF8/RAP80/Abraxas Journal of cell science High 23038782
2014 Phosphorylated RPA (phosphorylated by Cdk2 and ATR during replication fork stalling) recruits PALB2 to stalled replication forks. RPA phosphorylation increased localization of PALB2 and BRCA2 to RPA-bound nuclear foci during replication stress, and phosphorylated RPA stimulated recruitment of PALB2 to single-stranded DNA in a cell-free system. Loss of PALB2 or expression of phosphorylation-defective RPA2 led to significant DNA damage after replication stress, exacerbated by PARP inhibitors. Single-molecule fiber analysis, immunofluorescence foci analysis, cell-free RPA-ssDNA recruitment assay, phosphorylation-defective RPA2 mutant cells, PALB2 knockdown The Journal of cell biology High 25113031
2014 PALB2 and BRCA2 interact with DNA polymerase η (Polη) and colocalize with Polη at stalled or collapsed replication forks after hydroxyurea treatment. PALB2 and BRCA2 are required to sustain the recruitment of Polη at blocked replication forks and stimulate Polη-dependent DNA synthesis on D-loop substrates, implicating PALB2 in the initiation of recombination-associated DNA synthesis. Co-immunoprecipitation, immunofluorescence colocalization, Polη foci analysis upon PALB2/BRCA2 knockdown, in vitro D-loop DNA synthesis assay Cell reports High 24485656
2014 PALB2 recruitment to DNA double-strand breaks is via a ubiquitin-dependent signaling pathway involving RAP80, Abraxas, and BRCA1. PALB2 also interacts with RAD51C and DNA polymerase η, forming a network of tumor suppressors required for homologous recombination. Epistasis analysis, co-immunoprecipitation (review synthesizing experimental data from cited papers) Biochimica et biophysica acta Medium 24998779
2016 PALB2 is phosphorylated at three N-terminal S/Q sites by ATM and ATR kinases in response to ionizing radiation and hydroxyurea. A phospho-deficient PALB2 mutant is unable to support proper RAD51 foci formation and is less potent in homology-directed repair, whereas a phospho-mimicking PALB2 supports RAD51 foci formation. The PALB2-dependent checkpoint response is unaffected by phospho-deficient PALB2, revealing a separation of PALB2 functions. Site-directed mutagenesis of PALB2 S/Q sites, phospho-deficient and phospho-mimicking mutant reconstitution, RAD51 foci assay, HDR reporter assay, checkpoint assay EMBO reports High 27113759
2015 ATM phosphorylates PALB2 at Ser-157 and Ser-376 in response to ionizing radiation. Full phosphorylation also requires BRCA1, highlighting the importance of the BRCA1-PALB2 interaction in orchestrating DNA damage responses. Dysregulated PALB2 phosphorylation results in sustained activation of DNA damage responses. Mass spectrometry phosphorylation mapping, site-directed mutagenesis, ATM kinase inhibitor experiments, phospho-specific antibody, BRCA1 depletion The Journal of biological chemistry High 26420486
2017 RNF168 contains a PALB2-interacting domain (PID) that directly binds the WD40 domain of PALB2. PALB2 indirectly recognizes H2A ubiquitylation by physically associating with ubiquitin-bound RNF168. This RNF168-PALB2 interaction facilitates assembly of PALB2-containing HR complexes at DSBs in S/G2 cells, coupling PALB2-dependent homologous recombination to H2A ubiquitylation. Co-immunoprecipitation, domain mapping, HR reporter assay, immunofluorescence foci analysis, mutant reconstitution in PALB2-deficient cells eLife High 28240985
2017 The PALB2-BRCA1 interaction (via PALB2 N-terminal coiled-coil domain residue L35P in patients) is required for breast cancer suppression. The L35P variant abrogates the PALB2-BRCA1 interaction and completely disables PALB2's ability to promote HR and confer resistance to platinum salts and PARP inhibitors. Multiple additional germline variants in the PALB2 N-terminal BRCA1-binding domain affect HR function to varying degrees. Co-immunoprecipitation, HR assay, platinum/PARP inhibitor resistance assay, whole-exome sequencing of tumor (showing somatic second hit and HRD signature), segregation analysis Oncogene High 28319063
2017 PALB2 associates with active genes through MRG15, which recognizes histone H3 trimethylated at lysine 36 (H3K36me3) via the SETD2 methyltransferase. PALB2-MRG15 interaction mutations confer elevated sensitivity to the topoisomerase inhibitor camptothecin and increased DNA stress in gene bodies during replication. The steady-state presence of PALB2 at active genes via the SETD2/H3K36me3/MRG15 axis protects these regions during DNA replication. ChIP-seq, genome-wide analysis, missense mutant reconstitution of PALB2-MRG15 interface, camptothecin sensitivity assay, metaphase chromosome analysis, DNA fiber analysis Proceedings of the National Academy of Sciences of the United States of America High 28673974
2018 PALB2 connects BRCA1 and BRCA2 in the G2/M DNA damage checkpoint response. The BRCA1-PALB2 interaction contributes to checkpoint activation while the PALB2-BRCA2 complex is more critical for checkpoint maintenance. PALB2 checkpoint function is independent of CHK1 and CHK2 phosphorylation. Cells with disengaged BRCA1-PALB2 interaction show greatly increased chromosomal abnormalities after ionizing radiation due to combined defects in HR and checkpoint control. Flow cytometry checkpoint assay, PALB2 interaction mutant reconstitution (BRCA1-binding deficient vs BRCA2-binding deficient), chromosomal aberration analysis, CHK1/CHK2 inhibitor experiments Oncogene High 30337689
2018 The PALB2 N-terminal coiled-coil domain forms an antiparallel coiled-coil leucine zipper homodimer as determined by solution NMR spectroscopy. PALB2cc also forms heterodimers with the BRCA1 coiled-coil segment. Mutation of Leu24 in PALB2cc significantly reduces homodimer stability but has a more modest effect on PALB2cc/BRCA1cc heterodimer stability. Leu24 mutation leads to genomic instability and reduced cell viability after DNA double-strand break-inducing agents. Solution NMR spectroscopy, NMR chemical-shift perturbation studies, analytical ultracentrifugation, site-directed mutagenesis, clonogenic survival assay Biochemistry High 30289697
2019 PALB2 possesses a major DNA-binding site in its N-terminal DNA-binding domain (N-DBD). Mutations in this site reduce RAD51 foci formation and overall HDR efficiency in cells by ~50%. The N-DBD stimulates RAD51 recombinase function and also possesses strand exchange activity without RAD51, including the ability to use RNA substrates and stimulate inverse strand exchange. In vitro DNA binding assay, site-directed mutagenesis, RAD51 foci assay, HDR reporter assay in cells, in vitro strand exchange assay with purified recombinant protein eLife High 31017574
2019 USP22, a deubiquitinase, directly interacts with PALB2 through the C-terminal WD40 domain of PALB2. This interaction stimulates USP22 catalytic deubiquitinase activity in vitro. USP22 is required for BRCA2, PALB2, and RAD51 recruitment to DNA double-strand breaks, partly through USP22 stabilizing BRCA2 and PALB2 protein levels. Co-immunoprecipitation, in vitro deubiquitinase activity assay, siRNA knockdown, immunofluorescence foci analysis Molecular cancer research : MCR Medium 31685642
2020 In BRCA1-null/53BP1-depleted cells, PALB2 recruitment to resected DSBs is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region. In 53BP1-expressing cells, this acidic patch is occupied by 53BP1's ubiquitin-directed recruitment (UDR) domain, blocking PALB2 access. Loss of 53BP1 in BRCA1-deficient cells restores PALB2 accrual at DSBs in a PALB2- and BRCA2-dependent manner, partially restoring HR. BRCA1-null/53BP1-depleted cell model, ChAM domain mutation analysis, nucleosome acidic patch binding assay, RAD51 foci analysis, HR reporter assay Nature communications High 32041954
2021 RNF168-generated mono-ubiquitinated H2A (mUb-H2A) recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the coiled-coil domain-mediated BRCA1-PALB2 interaction. Epistatic analysis in mice harboring a Brca1CC mutation (blocking Brca1-Palb2 interaction) combined with Rnf168 loss disrupted development and reduced Palb2-Rad51 localization. Mouse genetic epistasis (Brca1CC × Rnf168 alleles), immunofluorescence foci analysis, Co-immunoprecipitation, domain interaction mapping Nature communications High 34408138
2021 BRCA1 and RNAi factors promote sdRNA (single-stranded DNA-damage-associated small RNA)-mediated DNA repair at transcriptional termination pause sites via the PALB2-RAD52 complex. sdRNAs promote DNA repair driven by PALB2-RAD52 at R-loop-rich sites with single-stranded DNA breaks, operating in both quiescent (G0) and proliferating cells. BRCA1/PALB2/RAD52 interaction studies, sdRNA characterization, genome-wide analysis, PALB2 depletion with repair readout Nature Medium 33536619
2022 Disruption of the BRCA1-PALB2 interaction causes persistent high levels of DNA damage in HCC cells, leading to activation of the cGAS-STING signaling pathway in both malignant hepatocytes and M1 macrophages. The activated cGAS-STING pathway induces PD-L1 expression via STING-IRF3-STAT1, causing immunosuppression, while also recruiting T lymphocytes through the STING-IRF3 pathway. Mouse model with disrupted BRCA1-PALB2 interaction, cGAS-STING pathway activation assays, immunofluorescence, PD-1 antibody treatment experiment, flow cytometry Hepatology (Baltimore, Md.) Medium 35006619
2014 Disruption of the BRCA1-PALB2 interaction in mice (hypomorphic Palb2 allele expressing BRCA1-binding-deficient PALB2) causes Fanconi anemia-like phenotype including hypersensitivity and chromosomal breakage with mitomycin C, reduced male fertility due to impaired meiosis, increased germ cell apoptosis, and significant defect in sex chromosome synapsis in meiocytes. Knock-in mouse model with BRCA1-binding-deficient PALB2, mitomycin C sensitivity and chromosomal breakage assay, fertility assay, meiotic spread analysis, germ cell apoptosis assay The Journal of biological chemistry High 25016020
2016 The BRCA2-PALB2 interaction (mediated by the N-terminal region of BRCA2) is essential for maintaining genomic integrity. Knock-in mice carrying Brca2G25R (a single amino acid change disrupting BRCA2-PALB2 interaction) show defects in body size, fertility, meiotic progression, genome stability, and increased tumor susceptibility. Severity increased with decreasing interaction, demonstrating that BRCA1-PALB2-BRCA2 complex formation and BRCA2's DNA-binding domain have overlapping roles in BRCA2 recruitment to DNA damage sites. Knock-in mouse model (Brca2G25R), combined with Palb2 and Trp53 heterozygosity, genomic instability assay, meiosis analysis, tumor surveillance, DNA damage recruitment assay PLoS genetics High 27490902
2013 The N-terminal segment of BRCA2 (PALB2-binding domain) and the DNA-binding domain (DBD) of BRCA2 play substantially overlapping roles in BRCA2 function. Loss of both domains (BRCA2ΔN+ΔDBD) phenocopies BRCA2-null cells, while single deletions show moderate phenotypes. Formation of the BRCA1-PALB2-BRCA2 complex and the DBD are both required for efficient BRCA2 recruitment to DNA damage sites. DT40 chicken cell gene targeting, double mutant epistasis, BRCA2 recruitment foci analysis, camptothecin/cisplatin/PARP inhibitor sensitivity assays Cancer research High 24285729
2014 BRCA1 and PALB2 co-occupy chromatin at actively transcribed genes genome-wide and are required for transcriptional responsiveness to NF-κB and retinoic acid. PALB2 plays a role in transcriptional co-activation in breast epithelial cells. ChIP-seq, genome-wide transcriptional analysis by RNA-seq, NF-κB and retinoic acid stimulation with BRCA1/PALB2 knockdown The EMBO journal Medium 24591564
2010 Homozygous deletion of Palb2 in mice causes embryonic lethality at E9.5 with defective mesoderm differentiation after gastrulation and increased p21 expression. Palb2-/- blastocysts show growth defect in vitro. The phenotype resembles Brca1 and Brca2 knockout mice, supporting the in vivo functional relationship of PALB2 with BRCA1 and BRCA2. Palb2 knockout mouse model, embryo phenotyping, immunohistochemistry for p21, blastocyst culture Human molecular genetics High 20484223
2020 Ablation of the Brca1-Palb2 interaction in mice (Brca1L1363P knock-in) causes Fanconi anemia-like phenotypes: hypersensitivity to DNA-damaging agents, failure to recruit Rad51 to DSBs, growth retardation, hyperpigmentation, skeletal abnormalities, male/female infertility, macrocytosis, and death from bone marrow failure or lymphoblastic lymphoma/leukemia. Knock-in mouse model (Brca1 L1363P), DNA damage sensitivity assay, Rad51 foci analysis, phenotypic characterization, survival analysis Cancer research High 32732220
2022 Pentagalloylglucose (PGG) disrupts the PALB2-BRCA2 protein-protein interaction by occupying a binding groove in the WD40 domain of PALB2 (tips of the fourth and fifth blades). PGG reduces BRCA2 recruitment to DNA damage sites and inhibits RAD51 foci formation, suppressing homologous recombination repair, and sensitizes cancer cells to PARP inhibitors and radiotherapy. Structure-based virtual screening, NanoBiT-based PPI assay, molecular docking, in vitro binding affinity assay, immunofluorescence foci analysis, clonogenic assay, xenograft tumor model Cancer letters High 35926819
2019 Functional analysis of 84 PALB2 missense variants of uncertain significance identified four variants (L24S, L35P, I944N, L1070P) that disrupt PALB2-mediated homology-directed repair. L24S and L35P disrupt BRCA1-PALB2 protein complexes; I944N causes protein instability; both I944N and L1070P mislocalize PALB2 to the cytoplasm. All four variants confer sensitivity to cisplatin and PARP inhibitors and reduce RAD51 foci formation. HDR reporter assay in Palb2 knockout mouse ES cells, Co-immunoprecipitation, protein stability assay, subcellular fractionation/localization, cisplatin and PARP inhibitor sensitivity, RAD51 foci assay Genetics in medicine : official journal of the American College of Medical Genetics High 31636395
2019 Functional analysis of 48 PALB2 VUS using cDNA-based HR rescue in Palb2 knockout mouse ES cells identified three VUS in the coiled-coil domain that abrogate BRCA1 interaction and several VUS in the WD40 domain that dramatically reduce protein stability. HR reporter assay in Palb2 knockout mouse ES cells, Co-immunoprecipitation for BRCA1 interaction, protein stability assay, cDNA complementation Nature communications High 31757951
2022 Loss of PALB2 in prostate cancer cell lines leads to decreased homologous recombination function (measured by loss of radiation-induced RAD51 foci and HR reporter assay) and significantly increased sensitivity to PARP inhibitors olaparib and rucaparib. siRNA/shRNA knockdown, RAD51 foci assay after irradiation, HR reporter assay, PARP inhibitor sensitivity assay (olaparib, rucaparib) in prostate cancer cell lines NPJ precision oncology Medium 35768576

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nature genetics 743 17200668
2014 Breast-cancer risk in families with mutations in PALB2. The New England journal of medicine 647 25099575
2009 PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Current biology : CB 443 19268590
2007 A recurrent mutation in PALB2 in Finnish cancer families. Nature 358 17287723
2015 Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. Journal of the National Cancer Institute 330 26315354
2019 Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 327 31841383
2020 Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 323 31976786
2009 PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Molecular cancer research : MCR 245 19584259
2007 Analysis of PALB2/FANCN-associated breast cancer families. Proceedings of the National Academy of Sciences of the United States of America 177 17420451
2012 PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Molecular and cellular biology 167 22331464
2010 PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer research 145 20858716
2015 Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. The Lancet. Oncology 136 25959805
2023 Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 117 36623243
2009 The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clinical cancer research : an official journal of the American Association for Cancer Research 115 19383810
2014 Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery. The Journal of cell biology 93 25113031
2011 PALB2 mutations in familial breast and pancreatic cancer. Familial cancer 93 21365267
2019 The Tumor Suppressor PALB2: Inside Out. Trends in biochemical sciences 90 30638972
2017 The Role of PALB2 in the DNA Damage Response and Cancer Predisposition. International journal of molecular sciences 82 28858227
2022 Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through cGAS-STING pathway. Hepatology (Baltimore, Md.) 79 35006619
2008 Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families. Breast cancer research and treatment 78 18302019
2017 Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. Journal of medical genetics 76 28779002
2014 Breast cancer proteins PALB2 and BRCA2 stimulate polymerase η in recombination-associated DNA synthesis at blocked replication forks. Cell reports 75 24485656
2011 BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast cancer research and treatment 75 21409391
2008 Promoter hypermethylation of the PALB2 susceptibility gene in inherited and sporadic breast and ovarian cancer. Cancer research 75 18281473
2022 BRCA1-Dependent and Independent Recruitment of PALB2-BRCA2-RAD51 in the DNA Damage Response and Cancer. Cancer research 71 35819255
2017 A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation. eLife 71 28240985
2017 Compromised BRCA1-PALB2 interaction is associated with breast cancer risk. Oncogene 71 28319063
2016 Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model. Genetics in medicine : official journal of the American College of Medical Genetics 69 27464310
2020 Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management. Frontiers in oncology 68 32185139
2010 MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks. Journal of cell science 68 20332121
2013 Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nature communications 67 24153426
2014 PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. Biochimica et biophysica acta 62 24998779
2014 Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice. The Journal of biological chemistry 60 25016020
2009 MRG15 is a novel PALB2-interacting factor involved in homologous recombination. The Journal of biological chemistry 58 19553677
2021 RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage. Nature communications 57 34408138
2016 ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function. EMBO reports 56 27113759
2012 PALB2 self-interaction controls homologous recombination. Nucleic acids research 54 22941656
2019 Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. Cancer 52 31206626
2019 Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2. Nature communications 51 31757951
2016 Interaction with PALB2 Is Essential for Maintenance of Genomic Integrity by BRCA2. PLoS genetics 51 27490902
2020 PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1. Nature communications 50 32041954
2010 PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast cancer research and treatment 48 21165770
2013 The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 46 24136930
2012 ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates DNA repair. EMBO reports 46 22193777
2020 Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. Journal of medical genetics 45 32546565
2020 Molecular characteristics of BRCA1/2 and PALB2 mutations in pancreatic ductal adenocarcinoma. ESMO open 45 33229504
2019 Homologous recombination DNA repair defects in PALB2-associated breast cancers. NPJ breast cancer 45 31428676
2019 Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. International journal of cancer 44 30720863
2017 MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress. Proceedings of the National Academy of Sciences of the United States of America 44 28673974
2018 PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response. Oncogene 42 30337689
2021 BRCA1 and RNAi factors promote repair mediated by small RNAs and PALB2-RAD52. Nature 41 33536619
2014 Genome-wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co-activation. The EMBO journal 41 24591564
2012 Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer. PloS one 41 23110154
2010 Inactivation of Palb2 gene leads to mesoderm differentiation defect and early embryonic lethality in mice. Human molecular genetics 41 20484223
2018 Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma. Scientific reports 39 29802286
2020 Cancer risk management among female BRCA1/2, PALB2, CHEK2, and ATM carriers. Breast cancer research and treatment 38 32445176
2013 Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families. Breast cancer research : BCR 37 23448497
2013 PALB2 and breast cancer: ready for clinical translation! The application of clinical genetics 36 23935381
2019 Functional characterization of 84 PALB2 variants of uncertain significance. Genetics in medicine : official journal of the American College of Medical Genetics 35 31636395
2018 Molecular analysis of PALB2-associated breast cancers. The Journal of pathology 33 29431189
2012 MDC1 and RNF8 function in a pathway that directs BRCA1-dependent localization of PALB2 required for homologous recombination. Journal of cell science 32 23038782
2021 PALB2 mutations and prostate cancer risk and survival. British journal of cancer 31 34006922
2014 Exploring the roles of PALB2 at the crossroads of DNA repair and cancer. The Biochemical journal 30 24870022
2011 Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges. Clinical chemistry and laboratory medicine 30 22505525
2019 Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report. Journal of medical genetics 29 30890586
2016 Frequency of pathogenic germline mutation in CHEK2, PALB2, MRE11, and RAD50 in patients at high risk for hereditary breast cancer. Breast cancer research and treatment 29 27783279
2015 Heterozygous PALB2 c.1592delT mutation channels DNA double-strand break repair into error-prone pathways in breast cancer patients. Oncogene 29 26640152
2017 Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia. Breast cancer research and treatment 28 28664506
2020 Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing. Cancer 27 32339256
2018 PALB2 (partner and localizer of BRCA2). Atlas of genetics and cytogenetics in oncology and haematology 27 31413733
2021 Genotype-cancer association in patients with Fanconi anemia due to pathogenic variants in FANCD1 (BRCA2) or FANCN (PALB2). Cancer genetics 26 34687993
2021 Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants. The Journal of pathology 25 34846068
2020 PALB2 Variants: Protein Domains and Cancer Susceptibility. Trends in cancer 23 33139182
2015 Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry. Breast cancer research and treatment 23 25575445
2023 Homologous Recombination Deficiency Landscape of Breast Cancers and Real-World Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Patients With Somatic BRCA1/2, Germline PALB2, or Homologous Recombination Deficiency Signature. JCO precision oncology 22 37992259
2022 PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer. NPJ precision oncology 22 35768576
2019 Novel RNA and DNA strand exchange activity of the PALB2 DNA binding domain and its critical role for DNA repair in cells. eLife 22 31017574
2016 Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic. Cancer genetics 22 27106063
2011 Germline PALB2 mutation analysis in breast-pancreas cancer families. Journal of medical genetics 22 21415078
2020 Clinicopathological Features and Outcomes in Individuals with Breast Cancer and ATM, CHEK2, or PALB2 Mutations. Annals of surgical oncology 21 32996020
2019 USP22 Interacts with PALB2 and Promotes Chemotherapy Resistance via Homologous Recombination of DNA Double-Strand Breaks. Molecular cancer research : MCR 21 31685642
2018 Antiparallel Coiled-Coil Interactions Mediate the Homodimerization of the DNA Damage-Repair Protein PALB2. Biochemistry 21 30289697
2016 A Survey of BRCA1, BRCA2, and PALB2 mutations in women with breast cancer in Trinidad and Tobago. Breast cancer research and treatment 21 27469594
2013 Compensatory functions and interdependency of the DNA-binding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex. Cancer research 21 24285729
2020 Ablation of the Brca1-Palb2 Interaction Phenocopies Fanconi Anemia in Mice. Cancer research 20 32732220
2017 Frequency of germline PALB2 mutations among women with epithelial ovarian cancer. Familial cancer 20 27631815
2017 PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. BMC medical genomics 20 28279176
2016 PALB2: research reaching to clinical outcomes for women with breast cancer. Hereditary cancer in clinical practice 20 27099641
2015 ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response. The Journal of biological chemistry 19 26420486
2014 Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada. Hereditary cancer in clinical practice 19 25225577
2009 PALB2 variants in hereditary and unselected Finnish prostate cancer cases. Journal of negative results in biomedicine 19 20003494
2022 Pentagalloylglucose disrupts the PALB2-BRCA2 interaction and potentiates tumor sensitivity to PARP inhibitor and radiotherapy. Cancer letters 18 35926819
2018 Surgery for BRCA, TP53 and PALB2: a literature review. Ecancermedicalscience 17 30174725
2017 Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer. Breast cancer research and treatment 17 28825143
2013 Hi-Plex for high-throughput mutation screening: application to the breast cancer susceptibility gene PALB2. BMC medical genomics 17 24206657
2023 The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib. Clinical cancer research : an official journal of the American Association for Cancer Research 16 37486343
2010 Association analysis of PALB2 and BRCA2 in bipolar disorder and schizophrenia in a scandinavian case-control sample. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 16 20872766
2014 Assessment of PALB2 as a candidate melanoma susceptibility gene. PloS one 15 24949998
2022 Identification and Management of Pathogenic Variants in BRCA1, BRCA2, and PALB2 in a Tumor-Only Genomic Testing Program. Clinical cancer research : an official journal of the American Association for Cancer Research 14 35363308
2015 Mutation analysis of PALB2 gene in French breast cancer families. Breast cancer research and treatment 14 26564480

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