Affinage

PALB2

Partner and localizer of BRCA2 · UniProt Q86YC2

Length
1186 aa
Mass
131.3 kDa
Annotated
2026-04-29
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PALB2 is a central scaffold in the homologous recombination (HR) DNA repair pathway that physically bridges BRCA1 and BRCA2 to coordinate RAD51-mediated strand invasion at DNA double-strand breaks and stalled replication forks. Its N-terminal antiparallel coiled-coil domain forms homodimers and heterodimers with BRCA1, while its C-terminal WD40 domain binds BRCA2; PALB2 is recruited to damage sites through an RNF168→BARD1/BRCA1 ubiquitin-dependent cascade supplemented by a chromatin-association motif (ChAM) and MRG15-dependent tethering to H3K36me3-marked active genes, where it directly stimulates RAD51 D-loop formation and polymerase η-mediated DNA synthesis (PMID:19268590, PMID:20871616, PMID:28240985, PMID:28673974, PMID:34408138, PMID:24485656). ATM/ATR phosphorylation of PALB2 at N-terminal S/Q sites promotes RAD51 nucleofilament assembly separately from checkpoint signaling, and PALB2 contributes to G2/M checkpoint maintenance through its BRCA1 and BRCA2 interactions (PMID:27113759, PMID:30337689). Beyond DNA repair, PALB2 competes with NRF2 for KEAP1 binding via an ETGE motif to regulate cellular redox homeostasis (PMID:22331464). Biallelic PALB2 mutations cause Fanconi anemia subtype FA-N, and monoallelic loss-of-function variants predispose to breast, pancreatic, and other cancers (PMID:17200668, PMID:17287723).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 High

    The identity of PALB2 as a BRCA2-interacting protein essential for its nuclear localization and DNA repair was established, and biallelic mutations were shown to cause Fanconi anemia subtype FA-N, revealing that BRCA2 function depends on an upstream binding partner.

    Evidence Protein interaction studies and genetic analysis of FA patients with functional complementation

    PMID:17200668

    Open questions at the time
    • Mechanism of PALB2-mediated BRCA2 nuclear import unknown
    • Relationship to BRCA1 not yet identified
    • Structural basis of PALB2-BRCA2 interaction undefined
  2. 2007 High

    The Finnish founder truncation c.1592delT demonstrated that loss of the BRCA2-binding C-terminus abolishes HR and interstrand crosslink repair, establishing structure-function requirements for the PALB2-BRCA2 axis.

    Evidence HR and crosslink repair assays with truncation mutants and BRCA2 co-immunoprecipitation

    PMID:17287723

    Open questions at the time
    • Whether PALB2 has repair functions independent of BRCA2 unknown
    • Cancer risk quantification from monoallelic truncation not mechanistically resolved
  3. 2009 High

    PALB2 was shown to physically and functionally bridge BRCA1 (via N-terminal coiled-coil) and BRCA2 (via C-terminus), with PALB2 homo-oligomerization and the BRCA1 interaction each required for focal accumulation at DSBs and HR repair, answering how BRCA1 and BRCA2 cooperate in the same pathway.

    Evidence Bacterially expressed fragment binding, co-IP, reconstitution of PALB2-deficient cells with domain mutants (L21P, L24P, Δ1-70), HR and mitomycin C assays, chromatin fractionation

    PMID:19268590 PMID:19423707 PMID:19584259

    Open questions at the time
    • Structural detail of the coiled-coil heterodimer not resolved
    • Relative contributions of homodimer versus heterodimer at DSBs unclear
    • Upstream signals recruiting PALB2 to chromatin unknown
  4. 2009 High

    MRG15 was identified as a direct PALB2 partner that governs HR template choice, showing that PALB2 has functions beyond simple BRCA1-BRCA2 bridging.

    Evidence Direct binding of purified proteins, sister chromatid exchange and gene conversion assays with MRG15-binding-defective PALB2 mutants

    PMID:19553677

    Open questions at the time
    • Chromatin mark recognized by MRG15 for PALB2 recruitment not yet defined
    • Whether MRG15-PALB2 operates genome-wide or at specific loci unknown
  5. 2010 High

    Purified PALB2 was shown to bind DNA and directly stimulate RAD51-mediated D-loop formation cooperatively with RAD51AP1, establishing that PALB2 is not merely a scaffold but an active biochemical stimulator of recombinase activity.

    Evidence In vitro D-loop assay, electron microscopy, pull-down with purified proteins

    PMID:20871616

    Open questions at the time
    • Which PALB2 domain mediates DNA binding not mapped
    • Whether stimulation of RAD51 requires BRCA2 in vivo not resolved
  6. 2010 High

    Palb2 knockout mice showed embryonic lethality at E9.5 phenocopying Brca1/Brca2 knockouts, confirming PALB2 is essential for mammalian development and epistatic with BRCA1/BRCA2.

    Evidence Mouse knockout model with embryonic staging, histology, p21 expression analysis

    PMID:20484223

    Open questions at the time
    • Cell-type-specific requirements for PALB2 not defined
    • Whether p21 upregulation is a direct or indirect consequence unclear
  7. 2012 High

    A chromatin-association motif (ChAM) was identified as necessary and sufficient for PALB2 chromatin binding, and PALB2 was placed in the MDC1→RNF8→RAP80→Abraxas→BRCA1 signaling cascade, resolving the upstream pathway that delivers PALB2 to DSBs.

    Evidence Chromatin fractionation with ChAM deletions, epistasis by siRNA of pathway components, HR reporter assays

    PMID:22193777 PMID:23038782

    Open questions at the time
    • Chromatin target of ChAM not biochemically identified
    • Relative contribution of ChAM versus BRCA1-dependent recruitment not quantified
  8. 2012 High

    PALB2 was discovered to compete with NRF2 for KEAP1 binding through an ETGE motif, regulating NRF2 nuclear accumulation and cellular ROS levels — revealing a non-repair tumor suppressor function in redox homeostasis.

    Evidence Direct binding with purified proteins, ETGE competition assay, ROS measurement, NRF2 reporter assay

    PMID:22331464

    Open questions at the time
    • Physiological impact of PALB2-KEAP1 interaction on tumorigenesis not demonstrated in vivo
    • Whether redox regulation feeds back on HR efficiency unknown
  9. 2014 High

    PALB2 was shown to function at stalled replication forks: phosphorylated RPA recruits PALB2-BRCA2 for fork recovery, and PALB2-BRCA2 stimulates polymerase η-dependent D-loop DNA synthesis, extending PALB2's role from DSB repair to replication stress tolerance.

    Evidence Single-molecule fiber analysis, cell-free recruitment assay with phospho-RPA, in vitro D-loop synthesis reconstitution, Polη co-IP

    PMID:24485656 PMID:25113031

    Open questions at the time
    • Whether PALB2-Polη interaction is direct or BRCA2-mediated not fully resolved
    • Fork protection versus fork restart contributions not separated
  10. 2014 High

    PALB2 was found to participate in G2/M checkpoint maintenance through BRCA1-PALB2-BRCA2 interactions, with depletion causing premature checkpoint abrogation via AURORA A-PLK1, and disruption of BRCA1-PALB2 in mice causing Fanconi anemia phenotypes including bone marrow failure and infertility.

    Evidence G2 checkpoint assay, AURORA A/PLK1 analysis after RNAi, knock-in mouse model with mitomycin C sensitivity and meiotic spread analysis

    PMID:21637299 PMID:25016020

    Open questions at the time
    • Molecular mechanism by which PALB2-BRCA2 restrains PLK1 activation unknown
    • Whether checkpoint and HR functions are separable in vivo not resolved
  11. 2016 High

    ATM/ATR phosphorylation of PALB2 at N-terminal S/Q sites was shown to specifically promote RAD51 foci and HDR without affecting checkpoint signaling, establishing a separation-of-function between phospho-regulated repair and checkpoint roles.

    Evidence Mass spectrometry phospho-mapping, phospho-deficient and phospho-mimetic mutants, RAD51 focus and HDR reporter assays with ATM/ATR inhibitors

    PMID:26420486 PMID:27113759

    Open questions at the time
    • Phosphatase(s) that reverse PALB2 phosphorylation not identified
    • Whether phosphorylation controls PALB2-BRCA1 versus PALB2-BRCA2 interactions not resolved
  12. 2017 High

    Two key recruitment mechanisms were clarified: RNF168 directly interacts with the PALB2 WD40 domain to link H2A ubiquitylation to HR complex assembly, and MRG15 tethers PALB2 to H3K36me3-marked active genes via SETD2 methylation to protect gene bodies from replication-associated damage.

    Evidence RNF168-PALB2 WD40 co-IP and pulldown with PID deletion mutants; PALB2 ChIP-seq at H3K36me3 loci with MRG15-binding-defective mutants and camptothecin sensitivity

    PMID:28240985 PMID:28673974

    Open questions at the time
    • Whether RNF168-PALB2 and BRCA2-PALB2 WD40 interactions are mutually exclusive not tested
    • Genome-wide impact of MRG15-PALB2 loss on mutation spectra not characterized
  13. 2018 High

    NMR structure determination revealed that the PALB2 N-terminal coiled-coil forms an antiparallel leucine-zipper homodimer that can switch to a BRCA1 heterodimer, providing the structural basis for understanding how cancer-associated coiled-coil mutations (L24, L35P) disable BRCA1 interaction and HR.

    Evidence Solution NMR, analytical ultracentrifugation, cell viability assays with L24 and L35P mutants

    PMID:28319063 PMID:30289697

    Open questions at the time
    • Full-length PALB2 structure not available
    • How homodimer-to-heterodimer switching is regulated in vivo unknown
  14. 2019 High

    Systematic functional classification of dozens of PALB2 missense variants of uncertain significance defined the landscape of damaging mutations: coiled-coil variants disrupt BRCA1 binding, WD40 variants reduce protein stability or cause cytoplasmic mislocalization, and all confer cisplatin/PARP inhibitor sensitivity.

    Evidence cDNA complementation in Palb2 KO mES cells, HDR reporter assay, co-IP, drug sensitivity and protein stability analysis across 84+ variants

    PMID:31636395 PMID:31757951

    Open questions at the time
    • Clinical pathogenicity classification for most VUS still requires population-level data
    • Variants affecting MRG15 or KEAP1 binding not systematically tested
  15. 2021 High

    The complete ubiquitin-dependent signaling chain was assembled: RNF168 mono-ubiquitylates H2A, BARD1 BUDR domain reads mUb-H2A, BARD1-BRCA1 recruits PALB2 via coiled-coil, and PALB2 loads RAD51 — resolving how DNA damage signaling initiates HR. Separately, PALB2 was found to partner with RAD52 in a small-RNA-guided repair pathway at transcription termination pause sites.

    Evidence In vivo epistasis with Brca1CC/Rnf168 KO mice, BARD1-BUDR domain mutation; small RNA sequencing with PALB2-RAD52 co-IP and repair assay

    PMID:33536619 PMID:34408138

    Open questions at the time
    • Whether PALB2-RAD52 repair operates independently of canonical HR not fully established
    • Regulation of BARD1-BUDR recognition step not characterized
  16. 2022 High

    Pharmacological disruption of the PALB2-BRCA2 interaction by pentagalloylglucose (PGG) targeting the WD40 domain phenocopied genetic PALB2 loss, validating the WD40-BRCA2 interface as a druggable target for sensitizing HR-proficient tumors to PARP inhibitors and radiotherapy.

    Evidence Structure-based virtual screening, NanoBiT PPI assay, RAD51 focus formation assay, tumor xenograft

    PMID:35768576 PMID:35926819

    Open questions at the time
    • PGG selectivity and off-target effects not fully characterized
    • Whether WD40-targeted disruption affects RNF168 binding not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of PALB2, the mechanism by which the ChAM domain recognizes chromatin, how the homodimer-to-BRCA1-heterodimer switch is regulated, and the physiological significance of PALB2's redox function in tumor suppression.
  • No full-length PALB2 structure available
  • ChAM chromatin target not biochemically identified
  • In vivo role of PALB2-KEAP1/NRF2 axis in tumorigenesis not demonstrated
  • Interplay between RNF168 and BRCA2 binding at the WD40 domain not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3 GO:0005694 chromosome 3
Pathway
R-HSA-73894 DNA Repair 8 R-HSA-1643685 Disease 4 R-HSA-69306 DNA Replication 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1640170 Cell Cycle 2
Partners
BRCA1BRCA2KEAP1MRG15POLHRAD51RAD52RNF168
Complex memberships
BRCA1-PALB2-BRCA2-RAD51PALB2-MRG15

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PALB2 encodes a protein that interacts with BRCA2 and is required for BRCA2's intranuclear localization and DNA repair function; biallelic mutations cause Fanconi anemia subtype FA-N. Protein interaction studies, genetic analysis of FA patients, functional complementation Nature genetics High 17200668
2007 The Finnish founder mutation c.1592delT in PALB2 produces a truncated protein with reduced BRCA2-binding capacity and is deficient in homologous recombination repair and DNA interstrand crosslink repair. Homologous recombination assay, crosslink repair assay, BRCA2 co-immunoprecipitation with truncation mutants Nature High 17287723
2009 PALB2 physically and functionally links BRCA1 and BRCA2: PALB2 directly binds BRCA1 through its N-terminal coiled-coil domain and BRCA2 through its C-terminus; BRCA1 recruits PALB2 to DNA damage sites, which in turn organizes BRCA2 and RAD51. Point mutants L21P and L24P or deletion Δ1-70 disrupt the PALB2-BRCA1 interaction and abolish HR repair. Co-immunoprecipitation, bacterially expressed fragment binding assays, RAD51/BRCA2/PALB2 focus assembly, HR repair assay with mitomycin C resistance, reconstitution in PALB2-deficient cells Current biology : CB High 19268590
2009 PALB2 independently interacts with BRCA1 (N-terminus) and BRCA2 (C-terminus) and mediates the physical interaction between BRCA2 and a C-terminal fragment of BRCA1; the PALB2-BRCA1 and PALB2-BRCA2 interactions are each required for resistance to mitomycin C and homologous recombination repair. Bacterially expressed fragment binding assay, co-immunoprecipitation, cell extracts from reconstituted PALB2-deficient cells with point mutants, HR repair assay Molecular cancer research : MCR High 19584259
2009 PALB2 exists as homo-oligomers; PALB2 oligomerization is essential for its focal accumulation at DNA double-strand breaks in vivo, and its chromatin association is a prerequisite for subsequent BRCA2 and RAD51 loading. The BRCA2-RAD51 repair complex accumulates at DSBs independently of known checkpoint proteins via PALB2. Co-immunoprecipitation for oligomerization, live-cell imaging of foci, chromatin fractionation, knockdown reconstitution The Journal of biological chemistry High 19423707
2009 MRG15, a chromodomain protein component of histone acetyltransferase-deacetylase complexes, directly interacts with PALB2; this interaction suppresses hyper-recombination (sister chromatid exchange and gene conversion), indicating PALB2-MRG15 governs template choice in HR. Co-immunoprecipitation, direct binding of purified proteins, sister chromatid exchange assay, gene conversion assay with MRG15-binding-defective PALB2 mutants The Journal of biological chemistry High 19553677
2010 PALB2 binds DNA and directly interacts with RAD51; PALB2 alone stimulates D-loop formation and, cooperatively with RAD51AP1, enhances RAD51-mediated synaptic complex assembly, revealing a direct role for PALB2 in stimulating RAD51 recombinase activity. In vitro D-loop assay, electron microscopy of synaptic complexes, pull-down with purified proteins, small-angle X-ray scattering Nature structural & molecular biology High 20871616
2010 MRG15 directly binds PALB2 and is required for recruitment of PALB2, BRCA2, and RAD51 to DNA damage sites and for chromatin loading of PALB2 and BRCA2; MRG15-deficient cells show reduced homology-directed repair and hypersensitivity to DNA interstrand crosslinkers, similar to PALB2- or BRCA2-deficient cells. Co-immunoprecipitation, pulldown with purified complexes, focus formation assay, chromatin fractionation, HR repair assay, drug sensitivity assay Journal of cell science High 20332121
2010 Systemic knockout of Palb2 in mice results in embryonic lethality at E9.5 with defective mesoderm differentiation and increased p21 expression, phenocopying Brca1 and Brca2 knockouts, demonstrating essential in vivo function of PALB2 in early development. Mouse knockout model, embryonic staging, histology, p21 expression analysis, blastocyst outgrowth assay Human molecular genetics High 20484223
2012 PALB2 directly interacts with KEAP1 via an ETGE-type motif shared with NRF2, competing 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, identifying PALB2 as a regulator of redox homeostasis. Co-immunoprecipitation, direct binding assay with purified proteins, ETGE motif competition assay, ROS measurement, NRF2 reporter assay, PALB2 knockdown/overexpression Molecular and cellular biology High 22331464
2012 The chromatin-association motif (ChAM), an evolutionarily conserved region in PALB2, is necessary and sufficient for PALB2 chromatin association in both unperturbed and DNA-damaged cells; deletion of ChAM reduces PALB2 and RAD51 accumulation at DNA damage sites and confers cellular hypersensitivity to mitomycin C. Chromatin fractionation, focus formation assay, ChAM deletion and domain-swap constructs, drug sensitivity assay EMBO reports High 22193777
2012 PALB2 localizes to DNA double-strand breaks via a pathway requiring MDC1, RNF8, RAP80, and Abraxas upstream of BRCA1; it is the BRCA1-PALB2 heterodimer, not the PALB2-PALB2 homodimer, that mediates HR and resistance to mitomycin C. Epistasis by siRNA knockdown of pathway components, PALB2 BRCT-fusion bypass constructs, HR reporter assay, drug sensitivity assay Journal of cell science High 23038782
2014 Phosphorylated RPA (by Cdk2 and ATR) recruits PALB2 to RPA-bound nuclear foci at stalled replication forks; this recruitment of PALB2 and BRCA2 is required for fork recovery, and loss of PALB2 leads to significant DNA damage after replication stress, accentuated by PARP inhibition. Single-molecule fiber analysis, immunofluorescence co-localization, cell-free recruitment assay with phospho-RPA, RPA2 phospho-deficient mutant cells, PALB2 knockdown The Journal of cell biology High 25113031
2014 PALB2 and BRCA2 interact with polymerase η (Polη), co-localize at stalled/collapsed replication forks, and stimulate Polη-dependent DNA synthesis on D-loop substrates; PALB2 and BRCA2 are required to sustain Polη recruitment at blocked replication forks. Co-immunoprecipitation of PALB2/BRCA2/Polη, co-localization by immunofluorescence, in vitro D-loop DNA synthesis assay, Polη focus formation in PALB2/BRCA2-depleted cells Cell reports High 24485656
2014 BRCA2 and BRCA1 are functionally connected through PALB2 in G2 checkpoint maintenance; depletion of PALB2 or BRCA2 leads to premature checkpoint abrogation and earlier activation of the AURORA A-PLK1 checkpoint-recovery pathway after ionizing radiation. RNAi screen, G2 checkpoint assay by flow cytometry, AURORA A/PLK1 activation analysis EMBO reports High 21637299
2014 PALB2 directly binds RAD51C (a RAD51 paralog) and pol η (translesion polymerase), placing PALB2 at the center of a network of tumor suppressor interactions that promote homologous recombination. Co-immunoprecipitation, pulldown assays (review with cited interaction data) Biochimica et biophysica acta Medium 24998779
2016 ATM and ATR phosphorylate PALB2 at three N-terminal S/Q sites in response to ionizing radiation and hydroxyurea; phospho-deficient PALB2 fails to support proper RAD51 foci formation and is less potent in homology-directed repair, while the checkpoint response remains intact, revealing a separation-of-function. Mass spectrometry phospho-mapping, phospho-deficient and phospho-mimetic PALB2 mutants, RAD51 focus formation assay, HDR reporter assay, ATM/ATR inhibitors EMBO reports High 27113759
2015 ATM phosphorylates PALB2 at Ser-157 and Ser-376 in response to ionizing radiation; full-blown PALB2 phosphorylation also requires BRCA1, and dysregulated phosphorylation results in sustained DNA damage response activation. Phospho-specific antibodies, ATM kinase inhibition, BRCA1 depletion, immunoprecipitation The Journal of biological chemistry High 26420486
2017 RNF168 directly interacts with PALB2 through a newly identified PALB2-interacting domain (PID) in RNF168 and the WD40 domain of PALB2; this interaction links PALB2-dependent homologous recombination to H2A ubiquitylation at DSBs in S/G2 cells and facilitates assembly of PALB2-containing HR complexes. Co-immunoprecipitation, pulldown with purified WD40 domain, PID deletion mutants, HR reporter assay, focus formation assay eLife High 28240985
2017 PALB2 missense variant L35P (c.104T>C) abrogates the PALB2-BRCA1 interaction through the coiled-coil domain, completely disabling HR repair and conferring sensitivity to platinum salts and PARP inhibitors; the tumor from the carrier shows somatic second-hit truncation and genomic hallmarks of HR deficiency. Co-immunoprecipitation for PALB2-BRCA1 interaction, HR reporter assay, drug sensitivity assay, whole-exome sequencing of tumor Oncogene High 28319063
2017 PALB2 associates with active genes through MRG15, which recognizes H3K36me3 deposited by SETD2 methyltransferase; PALB2 binding to MRG15 protects actively transcribed genes from genotoxic stress during replication, and disruption of this interaction increases camptothecin sensitivity and DNA damage in gene bodies. ChIP-seq for PALB2 and H3K36me3, PALB2-MRG15 binding-defective mutants, 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 The PALB2 N-terminal coiled-coil domain forms an antiparallel homodimer (classical leucine zipper) as determined by solution NMR; it can also form a heterodimer with the BRCA1 coiled-coil; mutation of Leu24 reduces homodimer stability more than heterodimer stability and leads to genomic instability and reduced viability after DSB induction. Solution NMR structure determination, NMR chemical-shift perturbation, analytical ultracentrifugation, cell viability assay after DSB-inducing agents Biochemistry High 30289697
2018 PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response: the BRCA1-PALB2 interaction contributes to checkpoint activation, while the PALB2-BRCA2 complex is more critical for checkpoint maintenance; disruption of BRCA1-PALB2 interaction causes increased chromosomal abnormalities due to combined HR and checkpoint defects. PALB2 checkpoint function is independent of CHK1 and CHK2 phosphorylation. G2/M checkpoint assay, BRCA1-PALB2 interaction-disrupting knock-in mouse cells, CHK1/CHK2 inhibition, chromosomal aberration analysis Oncogene High 30337689
2014 Disruption of the BRCA1-PALB2 interaction in mice (hypomorphic Palb2 allele with BRCA1-binding deficiency) causes FA-like phenotype including mitomycin C hypersensitivity, chromosomal breakage, and male infertility due to impaired meiosis and defective sex chromosome synapsis. Knock-in mouse model, mitomycin C sensitivity assay, meiotic spread analysis, chromosomal breakage assay The Journal of biological chemistry High 25016020
2020 Disruption of the BRCA1-PALB2 interaction causes persistent DNA damage in hepatocellular carcinoma cells, activating the cGAS-STING pathway in both malignant hepatocytes and M1 macrophages; this induces PD-L1 expression via STING-IRF3-STAT1 and T-lymphocyte recruitment via STING-IRF3, creating an immunosuppressive tumor microenvironment responsive to anti-PD-1 therapy. Brca1-Palb2 interaction-disrupted mouse HCC model, cGAS-STING pathway analysis, PD-L1 expression by IHC, anti-PD-1 treatment experiment, tumor-infiltrating lymphocyte analysis Hepatology (Baltimore, Md.) High 35006619
2021 RNF168-generated mono-ubiquitinated H2A (mUb-H2A) recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR); BARD1-BRCA1 then accumulates PALB2-RAD51 at DNA breaks via the coiled-coil domain-mediated BRCA1-PALB2 interaction, establishing the molecular chain connecting DNA damage signaling to HR repair. Epistasis with Brca1CC knock-in mice crossed to Rnf168 knockout, Palb2-Rad51 focus formation assay, BARD1-BUDR domain identification and mutation Nature communications High 34408138
2021 BRCA1 and RNAi proteins generate DNA damage-associated small RNAs (sdRNAs) at transcriptional termination pause sites; sdRNAs promote DNA repair driven by the PALB2-RAD52 complex at these R-loop-containing pause sites rich in single-stranded DNA breaks, operating in both quiescent and proliferating cells. Small RNA sequencing, PALB2-RAD52 co-immunoprecipitation, functional DNA repair assay at pause sites, cell-type-specific analysis Nature High 33536619
2019 Functional analysis of 48 PALB2 missense variants of uncertain significance using a cDNA-based HR rescue assay in Palb2 knockout mouse ES cells identified variants impairing function: three VUS in the coiled-coil domain abrogate BRCA1 interaction, while several WD40 domain VUS dramatically reduce protein stability. cDNA complementation assay in Palb2 KO mES cells, HR reporter assay, co-immunoprecipitation for BRCA1 interaction, protein stability analysis Nature communications High 31757951
2019 Functional characterization of 84 PALB2 missense VUS using a cellular HDR assay identified four variants (L24S, L35P, I944N, L1070P) that disrupt PALB2-mediated HDR, confer cisplatin and PARP inhibitor sensitivity, and reduce RAD51 foci formation; L24S and L35P disrupt BRCA1-PALB2 complex, I944N causes protein instability, and I944N and L1070P mislocalize PALB2 to the cytoplasm. HDR reporter assay, drug sensitivity assay, RAD51 focus formation, co-immunoprecipitation, protein localization by immunofluorescence Genetics in medicine : official journal of the American College of Medical Genetics High 31636395
2014 Genome-wide chromatin occupancy analysis shows PALB2 associates with highly active gene loci together with BRCA1 and plays a role in transcriptional responsiveness to NF-κB and retinoic acid signaling in breast epithelial cells. ChIP-seq, RNA-seq, PALB2/BRCA1 knockdown with gene expression analysis The EMBO journal Medium 24591564
2022 PALB2 or BARD1 loss in prostate cancer cell lines leads to decreased RAD51 foci formation after radiation, reduced HR capacity by reporter assay, and significantly increased sensitivity to PARP inhibitors olaparib and rucaparib, confirming PALB2 loss as a marker of HR deficiency and PARP inhibitor sensitivity. siRNA knockdown, radiation-induced RAD51 focus formation assay, HR reporter assay, PARP inhibitor drug sensitivity assay in multiple prostate cancer cell lines NPJ precision oncology High 35768576
2022 Pentagalloylglucose (PGG) occupies a binding groove in the tips of the fourth and fifth blades of the PALB2 WD40 domain to disrupt the PALB2-BRCA2 protein-protein interaction, reducing BRCA2 recruitment to DNA damage sites, inhibiting RAD51 foci formation and HR repair, and sensitizing tumors to PARP inhibitors and radiotherapy. Structure-based virtual screening, NanoBiT-based PPI assay, molecular docking, in vitro binding affinity assay, RAD51 focus formation assay, tumor xenograft assay Cancer letters High 35926819
2020 Disruption of the Brca1-Palb2 interaction in mice (Brca1 L1363P knock-in) causes Fanconi anemia phenotypes including growth retardation, skeletal abnormalities, infertility, macrocytosis, bone marrow failure, and lymphoblastic lymphoma/leukemia; MEF cells show hypersensitivity to DNA-damaging agents and failure to recruit Rad51 to DSBs. Knock-in mouse model (Brca1 L1363P), MEF drug sensitivity assay, Rad51 focus formation assay, hematopoietic analysis Cancer research High 32732220
2013 PALB2 haploinsufficiency in heterozygous mutation carrier lymphoblastoid cells causes aberrant DNA replication with increased origin firing and shorter inter-fork distances, elevated ATR protein levels, and aberrant CHK1/CHK2-mediated DNA damage responses, along with elevated chromosomal instability in primary blood lymphocytes. DNA fiber assay, Western blotting for ATR/CHK1/CHK2, chromosomal instability analysis of primary lymphocytes from PALB2 mutation carriers Nature communications High 24153426
2016 Disruption of BRCA2 interaction with PALB2 (Brca2 G25R knock-in mouse) causes defects in body size, fertility, meiosis, and genome stability, with increased tumor susceptibility; severity scales with degree of BRCA2-PALB2 interaction loss, demonstrating in vivo significance of this interaction for genomic integrity. Knock-in mouse model (Brca2 G25R), combined with Palb2 and Trp53 heterozygosity, fertility and meiotic analysis, tumor incidence, genome stability assays PLoS genetics High 27490902

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 741 17200668
2014 Breast-cancer risk in families with mutations in PALB2. The New England journal of medicine 640 25099575
2009 Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science (New York, N.Y.) 595 19264984
2009 PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Current biology : CB 438 19268590
2007 A recurrent mutation in PALB2 in Finnish cancer families. Nature 356 17287723
2015 Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. Journal of the National Cancer Institute 325 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 320 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 314 31976786
2009 PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Molecular cancer research : MCR 244 19584259
2014 BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genetics in medicine : official journal of the American College of Medical Genetics 232 25356972
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 165 22331464
2010 PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer research 145 20858716
2010 Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nature structural & molecular biology 137 20871616
2015 Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. The Lancet. Oncology 133 25959805
2007 Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast cancer research : BCR 123 18053174
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 114 19383810
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 113 36623243
2016 Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer. Gastroenterology 98 28024868
2010 A PALB2 mutation associated with high risk of breast cancer. Breast cancer research : BCR 98 21182766
2011 PALB2 mutations in familial breast and pancreatic cancer. Familial cancer 93 21365267
2014 Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery. The Journal of cell biology 92 25113031
2019 The Tumor Suppressor PALB2: Inside Out. Trends in biochemical sciences 90 30638972
2009 PALB2 regulates recombinational repair through chromatin association and oligomerization. The Journal of biological chemistry 87 19423707
2018 Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study. The lancet. Gastroenterology & hepatology 84 29706558
2017 The Role of PALB2 in the DNA Damage Response and Cancer Predisposition. International journal of molecular sciences 80 28858227
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
2022 Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through cGAS-STING pathway. Hepatology (Baltimore, Md.) 77 35006619
2017 Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. Journal of medical genetics 75 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
2017 A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation. eLife 71 28240985
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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
2011 Plasticity of BRCA2 function in homologous recombination: genetic interactions of the PALB2 and DNA binding domains. PLoS genetics 69 22194698
2010 MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks. Journal of cell science 67 20332121
2013 Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nature communications 66 24153426
2020 Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management. Frontiers in oncology 64 32185139
2014 PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. Biochimica et biophysica acta 62 24998779
2011 A genetic screen identifies BRCA2 and PALB2 as key regulators of G2 checkpoint maintenance. EMBO reports 62 21637299
2022 BRCA1-Dependent and Independent Recruitment of PALB2-BRCA2-RAD51 in the DNA Damage Response and Cancer. Cancer research 60 35819255
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 57 19553677
2021 RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage. Nature communications 55 34408138
2016 ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function. EMBO reports 55 27113759
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 51 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
2018 Retrospective Survival Analysis of Patients With Advanced Pancreatic Ductal Adenocarcinoma and Germline BRCA or PALB2 Mutations. JCO precision oncology 49 35135099
2010 PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast cancer research and treatment 48 21165770
2012 ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates DNA repair. EMBO reports 46 22193777
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
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 44 24136930
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 43 28673974
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 42 30720863
2018 PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response. Oncogene 42 30337689
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 41 32546565
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
2011 Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Human mutation 41 21618343
2010 Inactivation of Palb2 gene leads to mesoderm differentiation defect and early embryonic lethality in mice. Human molecular genetics 41 20484223
2021 BRCA1 and RNAi factors promote repair mediated by small RNAs and PALB2-RAD52. Nature 40 33536619
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 37 32445176
2013 Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families. Breast cancer research : BCR 37 23448497
2009 A PALB2 germline mutation associated with hereditary breast cancer in Italy. Familial cancer 37 19763884
2019 Functional characterization of 84 PALB2 variants of uncertain significance. Genetics in medicine : official journal of the American College of Medical Genetics 34 31636395
2018 Molecular analysis of PALB2-associated breast cancers. The Journal of pathology 33 29431189
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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 30 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
2010 PALB2: a novel inactivating mutation in a Italian breast cancer family. Familial cancer 28 20852946
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 27 28664506
2012 Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families. Familial cancer 27 22692731
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2015 Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry. Breast cancer research and treatment 23 25575445
2014 PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo. Genetics in medicine : official journal of the American College of Medical Genetics 23 24556926
2014 A novel PALB2 truncating mutation in an Italian family with male breast cancer. Oncology reports 23 25529982
2022 PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer. NPJ precision oncology 22 35768576
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2011 Germline PALB2 mutation analysis in breast-pancreas cancer families. Journal of medical genetics 22 21415078
2018 Antiparallel Coiled-Coil Interactions Mediate the Homodimerization of the DNA Damage-Repair Protein PALB2. Biochemistry 21 30289697
2016 Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic. Cancer genetics 21 27106063
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
2014 Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe. Familial cancer 21 24061862
2013 Compensatory functions and interdependency of the DNA-binding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex. Cancer research 21 24285729
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 20 37992259
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
2015 ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response. The Journal of biological chemistry 19 26420486
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