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palb2

Properties1
aliasesPALB2, FANCN, FA-N, Partner and Localizer of BRCA2

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PALB2 (Partner and Localizer of BRCA2)

PALB2 is a nuclear scaffold protein that physically bridges brca1 and brca2 to enable homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs). It is the essential molecular coupler of the BRCA1–PALB2–BRCA2–RAD51 repair axis: without PALB2, BRCA2 cannot localize to chromatin damage sites and HR collapses. Monoallelic germline mutations confer breast, pancreatic, and ovarian cancer susceptibility at penetrance broadly comparable to BRCA2; biallelic loss causes Fanconi anemia subgroup N (FA-N), a rare pediatric bone marrow failure and cancer predisposition syndrome. In the aging context, PALB2 is a critical node of HR-pathway competence — a capacity that declines with age in hematopoietic stem cells and other regenerative compartments.

Identity

FieldValue
UniProtQ86YC2 (PALB2_HUMAN; Swiss-Prot reviewed)
NCBI Gene79728
HGNC26144
EnsemblENSG00000083093
Gene symbolPALB2 (synonym: FANCN)
Chromosomal location16p12.2
Canonical sequence length1,186 amino acids
Mouse orthologPalb2
GenAge entryNot listed (null) needs-canonical-id

UniProt entry last updated January 28, 2026. Evidence level: protein.

Structure and functional domains

PALB2 is organized around three mechanistically distinct regions:

N-terminal coiled-coil / oligomerization domain (CC: residues 9–41; oligomerization region: residues 1–160) The coiled-coil proper spans residues 9–41 (UniProt Q86YC2); the broader N-terminal region (1–160) is required for oligomerization and focal concentration at DNA damage sites. This region also carries the BRCA1-interaction interface (residues 1–319). PALB2 self-associates through this domain when not engaged by BRCA1; BRCA1 binding displaces the self-association and opens the complex for HR-scaffold assembly. RAD51 also contacts this region (residues 1–200), enabling a direct BRCA1-independent contribution to RAD51 loading.

Chromatin-association motif (ChAM; residues 395–446) A short domain that enables direct nucleosome binding, contributing to PALB2’s chromatin recruitment independent of its protein interactions. Loss of ChAM function impairs PALB2 localization to damaged chromatin.

C-terminal WD40 β-propeller (residues 854–1186) Seven WD40 repeats form a canonical β-propeller that mediates BRCA2 binding, RAD51C binding, and interaction with the translesion polymerase POLH (residues 775–1186). This domain is the anchor for the downstream HR effector complex.

Post-translational modifications Eight phosphorylation sites confirmed: Ser172, Ser190, Ser285, Ser376, Ser387, Ser454, Ser660, Ser781. Functional significance of individual sites is incompletely characterized. no-mechanism for most individual phosphorylation events.

Function: HR scaffold

PALB2 is the obligate linker of the two master HR proteins:

  1. BRCA1 (via N-terminal CC domain) recruits PALB2 to the DSB site in S/G2 phase
  2. PALB2 (via C-terminal WD40) recruits BRCA2 to chromatin
  3. BRCA2 loads RAD51 onto RPA-coated resected ssDNA, initiating strand invasion and template-directed repair

This BRCA1–PALB2–BRCA2 axis was established by Xia et al. (2006), who demonstrated that depletion of PALB2 abolished BRCA2 nuclear-foci formation at damage sites and phenocopied BRCA2 loss for HR sensitivity 1. Without PALB2, BRCA2 is physically excluded from damaged chromatin — the scaffold function is not redundant.

PALB2 also participates in HR outside the strict BRCA1-dependent pathway: its direct RAD51 contact (N-terminal, residues 1–200; UniProt Q86YC2) and chromatin-binding (ChAM) provide BRCA1-independent HR contributions. needs-replication — the specific contribution of PALB2’s BRCA1-independent RAD51 interaction to HR efficiency in cells has not been quantified in Xia 2006 (which focuses on BRCA2 chromatin localization); it is inferred from structural and biochemical data.

Function: replication fork context

PALB2’s role in protecting stalled replication forks from nucleolytic degradation is mechanistically distinct from its HR scaffold role and remains an area of active investigation. Daza-Martin et al. (2019) showed that the canonical BRCA1–PALB2 interaction is not required for fork protection — instead, the BRCA1–BARD1 complex (not the BRCA1–PALB2 interface) is the relevant fork-protective unit 2. contradictory-evidence — earlier models inferred PALB2-dependent fork protection from PALB2 knockdown effects on fork stability, but the 2019 Nature paper dissects the molecular requirement more precisely.

Discovery

Xia et al. (2006) identified PALB2 as a BRCA2 interactor by co-immunoprecipitation and named it “Partner and Localizer of BRCA2” 1. The same year (published online December 2006, print February 2007), Reid et al. showed that biallelic PALB2 mutations in 7 unrelated families caused a Fanconi anemia-like syndrome with cellular hypersensitivity to mitomycin C, establishing PALB2 as the Fanconi anemia complementation group N (FANCN) gene 3. The canonical FA genetic naming (FANCN = PALB2) is therefore distinct from FANCD1 (= BRCA2) and FANCJ (= BRIP1).

Disease: monoallelic germline mutations

Breast cancer susceptibility

Monoallelic loss-of-function mutations in PALB2 are established high-to-moderate penetrance breast cancer susceptibility alleles. The canonical penetrance estimate from Antoniou et al. (2014), analyzing 362 female PALB2 mutation carriers from 154 families: cumulative breast cancer risk by age 70 was 33% (95% CI 25–44%) with no affected first-degree relatives, rising to 58% (95% CI 50–66%) with two or more affected first-degree relatives diagnosed at age 50 or younger 4. By age 50, absolute risk was 14% (95% CI 9–20%). The mean cumulative risk across all carriers (without family history adjustment) was 35% (95% CI 26–46%) by age 70.

Relative risk vs. population background was ~8–9x in women under 40, declining to ~5x by age 60+ — demonstrating highest relative risk in early-onset context, mirroring BRCA1/2 biology 4.

Extrapolation dimensionStatus
Pathway conserved across populations?yes — confirmed across European, North American, and limited Asian cohorts
Family-history effect replicated?yes — stratified analysis in Antoniou 2014
Men included?partial — male breast cancer association documented but penetrance not estimated in Antoniou 2014

Pancreatic and ovarian cancer

PALB2 germline mutations confer ~3–5-fold elevated pancreatic ductal adenocarcinoma risk (UniProt disease annotation PNCA3). Ovarian cancer risk is elevated above population baseline but substantially lower than for BRCA1/2. NCCN guidelines (approximately 2023 update) added PALB2 to genetic-testing panels and to eligibility criteria for PARP inhibitor therapy in advanced breast cancer 5.

Disease: biallelic loss — Fanconi anemia subgroup N (FA-N)

Biallelic PALB2 mutation causes FA-N, a severe Fanconi anemia phenotype 3. Key features:

  • Bone marrow failure (pancytopenia) in childhood
  • Congenital abnormalities (skeletal, renal)
  • Markedly elevated pediatric cancer risk, including medulloblastoma and Wilms tumor
  • Cellular hypersensitivity to DNA crosslinking agents (mitomycin C confirmed in Reid 2007; cisplatin sensitivity is characteristic of FA broadly but not specifically demonstrated in FA-N by Reid et al.) — MMC sensitivity is the diagnostic test
  • Progeria-like features: bone marrow failure and growth retardation as segmental aging phenotype

FA-N fits within the broader FA genetic complementation framework: the FA core complex ubiquitinates FANCD2 and FANCI (ID2 complex), which in turn recruit downstream HR factors including PALB2 (FANCN) and BRCA2 (FANCD1) to resolve crosslink-induced DSBs. Loss of any FA gene blocks this cascade at or upstream of the ID2 monoubiquitination checkpoint. See fanconi-anemia-pathway for pathway-level context.

Aging relevance

HR-pathway decline in aging hematopoietic stem cells

Aging hematopoietic stem cells (HSCs) accumulate DNA damage progressively, as demonstrated by Rossi et al. (2007): quiescent HSCs attenuate DNA damage checkpoints and permit lesion accumulation, which becomes functionally deleterious when these cells are activated for regeneration 6. PALB2 is a rate-limiting node in the HR pathway that would be expected to contribute to this repair-capacity decline, though no direct HSC-specific PALB2 aging study has been published as of 2026-05-13. needs-human-replication

Mouse knockout phenotype

Homozygous Palb2 knockout in mice is embryonic lethal by E9.5, with defective mesoderm differentiation after gastrulation 7. This parallels Brca1 and Brca2 knockouts and underscores PALB2’s essential developmental role in HR-dependent genome maintenance. Heterozygous Palb2+/− mice develop normally through at least 8 months with no tumor predisposition over that short observation window 7. Conditional tissue-specific knockouts have not been systematically published for the aging context. needs-human-replication

FA-N as segmental progeria

FA-N patients present with hallmarks that overlap with segmental aging syndromes: bone marrow failure, reduced regenerative capacity, and elevated cancer risk — the same triad seen in Werner syndrome, Cockayne syndrome, and other DNA-repair-deficiency progerias. This positions PALB2 within the broader principle that HR competence is a longevity determinant.

Connection to HR-longevity biology

Comparative aging biology implicates enhanced HR as a longevity mechanism: long-lived species (naked mole rats, bowhead whales) show elevated DNA repair capacity relative to shorter-lived rodents. See homologous-recombination for the general framework. PALB2 as the BRCA1–BRCA2 bridge is one of the mechanistically tractable nodes in this pathway. No direct intervention targeting PALB2 expression for longevity has been tested.

Pathway membership and interactors

Pathway membership:

Key interactors (UniProt Q86YC2 experimental evidence):

PartnerDomain on PALB2Function
BRCA1N-terminal (1–319)Chromatin recruitment; HR initiation
BRCA2C-terminal WD40 (854–1186)BRCA2 chromatin localization; RAD51 loading
RAD51N-terminal (1–200)Direct RAD51 stabilization
RAD51CC-terminal WD40Variant HR (RAD51 paralogs)
MRG15 (MORF4L1)ChAM regionChromatin recruitment via H3K36me3-modified nucleosomes
KEAP1—Oxidative stress regulatory interaction (contested) contradictory-evidence
POLHC-terminal (775–1186)Translesion synthesis at stalled forks
USP11—Deubiquitylase; may modulate PALB2 stability
ERCC5 (XPG)—Nucleotide excision repair crosstalk

Druggability

Cancer context (tier 1 indication-bound)

PARP inhibitors exploit synthetic lethality in HR-deficient tumors. Tung et al. (2020) — the TBCRC 048 Phase II trial — demonstrated 82% objective response rate (ORR) in patients with germline PALB2 mutations treated with olaparib monotherapy (n=13 evaluable), with median PFS 13.3 months 5. This is the highest ORR reported for any single-gene-defined cohort in that trial, including sBRCA1/2 (50% ORR). Clinical-stage PARP inhibitors with PALB2-relevant evidence include olaparib, talazoparib, niraparib, and rucaparib.

NCCN guidelines now recognize PALB2 alongside BRCA1/2 for PARP inhibitor eligibility in advanced HER2-negative breast cancer.

Aging-context druggability (tier 3)

No aging-indication intervention targets PALB2 directly. The protein lacks a known small-molecule binding pocket amenable to activation; it functions as a scaffold. Possible indirect approaches (e.g., upregulating PALB2 expression to boost HR in aged HSCs) are speculative and untested. Druggability tier 3 reflects the absence of any aging-validated probe or clinical trial in an aging indication.

Note: The tier 1 oncology designation (PARP-inhibitor synthetic-lethality) is indication-bound — it applies to PALB2-deficient tumor cells, not to the aging-biology context in which one would want to enhance PALB2 function, not exploit its loss. Per CLAUDE.md R26/R27 aging-context convention, aging-context tier = 3.

Limitations and gaps

  • #gap/needs-human-replication — whether PALB2 expression or activity declines in aging human tissues (especially HSCs and regenerative compartments) has not been directly measured; aging-context data are inferred from model systems and FA-N phenotypes
  • #gap/no-mechanism — how age-associated changes in chromatin state or PTM landscape affect PALB2 ChAM binding and HR efficiency
  • #gap/needs-human-replication — conditional tissue-specific Palb2 knockouts in aging contexts (post-developmental) have not been published; Rantakari 2010 only shows heterozygotes are grossly normal to 8 months
  • #gap/contradictory-evidence — PALB2’s role in replication fork protection is mechanistically disputed (Daza-Martin 2019 vs earlier models); the exact extent to which PALB2 (vs BRCA1-BARD1) protects stalled forks requires resolution
  • #gap/needs-canonical-id — PALB2 does not appear in GenAge (HAGR); if an entry is added in future database updates, genage-id: should be populated
  • #gap/needs-gtex-query — gtex-aging-correlation: not populated; GTEx v2 API lookup needed for tissue-by-age expression profile

Footnotes

Footnotes

  1. doi:10.1016/j.molcel.2006.05.022 · Xia B et al. (Mol Cell 2006) · in-vitro (human cell lines: HeLa, U2OS, WI38, 293T, MCF10A) · n=multiple cell lines · discovery paper identifying PALB2 (FLJ21816) as BRCA2 nuclear binding partner by co-IP; demonstrates BRCA2 localization collapse and HR reduction (~3-fold by DR-GFP assay) on PALB2 siRNA depletion; PALB2 promotes stable BRCA2 association with chromatin (P100/S420 fractions); PALB2 siRNA phenocopies BRCA2 siRNA for MMC sensitivity and intra-S checkpoint; BRCA2 N-terminal residues 10–40 contain the PALB2-binding motif · archive: locally downloaded at ↩ ↩2

  2. doi:10.1038/s41586-019-1363-4 · Daza-Martin M et al. (Nature 2019; “Isomerization of BRCA1-BARD1 promotes replication fork protection”) · in-vitro (human cells) · PMID:31270457 · canonical BRCA1–PALB2 interaction NOT required for fork protection; BRCA1–BARD1 complex (regulated by PIN1-mediated conformational change) is required; BRCA1-BARD1 enhances RAD51 at stalled forks; cancer-associated BRCA1-BARD1 variants identified that impair fork protection but retain HR proficiency · archive: download in progress at verification time; verified via PubMed abstract ↩

  3. doi:10.1038/ng1947 · Reid S et al. (Nat Genet 2007; published online Dec 2006) · in-vitro + patient cells · n=7 unrelated FA families (7 affected individuals with PALB2 mutations sequenced from 82 FA probands; 4 had direct biallelic confirmation, 3 confirmed via parental samples) · biallelic PALB2 mutations → FA-N; mitomycin C sensitivity; normal FANCD2 monoubiquitination (downstream of FA core complex) · archive: locally downloaded at ↩ ↩2

  4. doi:10.1056/NEJMoa1400382 · Antoniou AC et al. (NEJM 2014) · observational (family cohort, modified segregation analysis) · n=154 families eligible after ascertainment adjustment (175 with ≥1 affected member; 362 female PALB2 mutation carriers analyzed, 229 with breast cancer) · cumulative breast cancer risk by 70: 33% (95% CI 25–44%; no FHx) to 58% (95% CI 50–66%; ≥2 FDRs with BC at age 50); mean across all carriers 35% (26–46%); relative risk 8–9x in women <40, 6–8x at 40–60, ~5x at 60+ vs UK background incidence 1993–1997 · archive: locally downloaded at ↩ ↩2

  5. doi:10.1200/JCO.20.02151 · Tung NM et al., TBCRC 048 (J Clin Oncol 2020) · phase-2 trial · n=13 evaluable gPALB2 patients · olaparib ORR 82% (highest of any cohort in trial); median PFS 13.3 months · archive: not OA; no local PDF ↩ ↩2

  6. doi:10.4161/cc.6.19.4759 · Rossi DJ et al. (Cell Cycle 2007) · PMID:17700071 · in-vivo (murine HSCs) + in-vitro · review/perspective · quiescent (G0) HSC status attenuates checkpoint control and DNA damage responses; aged murine HSCs maintain numerical reserves despite genomic damage accrual; functional capacity severely impaired under stress/regeneration conditions; mechanism: quiescence cytoprotects but permits lesion accumulation · archive: PDF download failed; verified via PubMed abstract (PMID:17700071) ↩

  7. doi:10.1093/hmg/ddq207 · Rantakari P et al. (Hum Mol Genet 2010) · PMID:20484223 · in-vivo (mouse knockout) · homozygous Palb2 null: embryonic lethal by E9.5 at latest, smaller and developmentally retarded, defective mesoderm differentiation after gastrulation; p21 (CDKN1A) expression increased; blastocysts show growth defect in vitro; heterozygous Palb2+/− mice normal and fertile, no macroscopic tumors through 8 months follow-up · phenotype parallels Brca1 and Brca2 knockouts · archive: PDF download failed (bronze OA); verified via PubMed abstract (PMID:20484223) ↩ ↩2

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