PALB2 (FANCN) — AIGR vs Affinage
Affinage record: run 2026-06-10 · 35 discoveries · self-eval pairwise = win, faith 100% · gates passed.
The Affinage record for PALB2 is a strong, PMID-dense (35 citations) mechanistic narrative of the
HR-scaffold life cycle: the N-terminal antiparallel coiled-coil leucine zipper binding BRCA1 (and the
homodimer→heterodimer switch that gates HR), the C-terminal WD40 β-propeller binding BRCA2, ubiquitin-
signaling recruitment to breaks (MDC1/RNF8/RAP80/Abraxas → BRCA1; RNF168-generated ub-H2A read by
BARD1-BRCA1; direct RNF168-PID/WD40 binding), intrinsic DNA/chromatin binding (N-DBD strand exchange;
ChAM–acidic-patch engagement antagonized by 53BP1), steady-state residence at active genes via
MRG15/SETD2/H3K36me3, stalled-fork recruitment by phospho-RPA and POLη support, ATM/ATR phospho-
regulation and a CHK1/CHK2-independent G2/M checkpoint, the KEAP1-NRF2 antioxidant branch, and a large
patient-variant/mouse-model layer (L24S/L35P/I944N/L1070P, Brca1-CC and Brca2-G25R knock-ins). The
AIGR review is curated, GOA-grounded, validated, and was already the product of a careful A→Z manual
pass with core_functions centered on the adaptor and DNA-binding activities.
Agreement (brief)
The two sources agree on the core biology. Both center PALB2 as the molecular adaptor/scaffold that
physically bridges BRCA1 (N-terminal coiled-coil) and BRCA2 (C-terminal WD40 propeller) to form the
BRCA1-PALB2-BRCA2 complex that localizes/stabilizes BRCA2 and loads RAD51 for HR (AIGR:
GO:0060090 molecular adaptor activity core, GO:0000724 ACCEPT across IBA/IEA/IDA/IMP, GO:1990391
DNA repair complex; Affinage narrative + PMID:19369211/19584259/24141787). Both agree on intrinsic
N-terminal DNA binding stimulating RAD51 strand invasion (AIGR GO:0003677/GO:0003697 ACCEPT, second
core function; Affinage PMID:20871616/31017574), coiled-coil homodimerization (GO:0042803 ACCEPT;
PMID:22941656/39584160), and nucleoplasmic/nuclear-foci localization. Both explicitly demote the same
secondary roles to non-core: KEAP1-NRF2 antioxidant signaling, POLη support at blocked forks, and
MRG15/MORF4L1 chromatin targeting.
Disagreements
| Topic | Affinage says | AIGR review says | Verdict (who is right + why) |
|---|---|---|---|
| Mechanism-profile GO layer | molecular_activity includes GO:0140097 catalytic activity, acting on DNA and GO:0098772 molecular function regulator activity |
PALB2 is not a catalytic enzyme; MF captured as GO:0060090 adaptor + GO:0003677/0003697 DNA/ssDNA binding |
AIGR right. Affinage's own header flags this layer as coarse/collapsed-to-parents. catalytic activity, acting on DNA is wrong-branch — PALB2 has no established catalytic activity (its "strand exchange" is a DNA-binding/annealing property, not an enzyme reaction); molecular function regulator activity is a generic parent of the specific RAD51-stimulation captured via DNA binding. Not imported. |
| "Histone binding" for ChAM | Lists GO:0042393 histone binding |
Now annotated GO:0031491 nucleosome binding (NEW, non-core) |
AIGR right (and more precise). The ChAM paper explicitly states "direct DNA or core histone binding was not detectable" while "ChAM robustly binds to nucleosomes." Histone binding is the wrong term; nucleosome binding is the correct, evidenced one — added here as a NEW annotation. |
| RNA binding | Lists GO:0003723 RNA binding |
Not annotated | Both partly right; AIGR conservative. The N-DBD does have in-vitro RNA strand-exchange/binding activity (PMID:31017574 "Novel RNA and DNA strand exchange activity"), so the claim is not baseless — but it is a specialized in-vitro property with no established in-vivo RNA-binding role, so AIGR reasonably omits it rather than over-annotate. Flagged as a minor gap, not incorporated. |
| Transcription / gene expression | mechanism_profile Reactome R-HSA-74160 Gene expression; narrative cites BRCA1-PALB2 co-occupancy at active genes and NF-κB/RA transcriptional co-activation (PMID:24591564) |
Not annotated to transcription | AIGR right to exclude as core. Transcriptional co-activation is a single-lab, less-replicated secondary observation; the chromatin residence it depends on is better captured as nucleosome/MRG15 chromatin targeting. Correctly out of the core MF/BP set. |
| Ubiquitin-recruitment cascade, ATM/ATR phospho, G2/M checkpoint, cGAS-STING/PD-L1 | Narrated as PALB2 mechanism (RNF168/RNF8/MDC1/RAP80; S/Q phosphosites; checkpoint; HCC immune signaling) | Not annotated as PALB2 functions | AIGR right. These are upstream regulators of PALB2 recruitment, post-translational regulation of PALB2, or downstream consequences of PALB2 loss — not molecular functions/processes PALB2 itself enables. Correctly out of scope; the G2/M checkpoint role is a defensible but minor omission. |
| KEAP1-NRF2 secondary role sourcing | Anchored to the primary mechanistic paper PMID:22331464 | Present (description + over-annotated interaction rows) but cited only via high-throughput interactomes | Affinage right that primary evidence exists. Incorporated: PMID:22331464 added as a reference and as supported_by on the KEAP1 interaction row, grounding a role that previously rested only on HuRI/BioPlex hits. |
Papers incorporated into the review
| PMID | Supports | How used |
|---|---|---|
| PMID:22193777 | Nucleosome binding (NEW GO:0031491) |
Bleuyard et al. 2012 EMBO Rep (ChAM). Full text confirms ChAM is necessary and sufficient for intrinsic chromatin association and "robustly binds to nucleosomes" (distinct from the DNA-binding regions). Added a NEW, non-core GO:0031491 nucleosome binding annotation with two verbatim supported_by quotes; upgraded the reference with reference_review (HIGH/VERIFIED). Term verified as a molecular_function via QuickGO. |
| PMID:22331464 | KEAP1-NRF2 secondary role (GO:0005515 KEAP1 row) |
Ma et al. 2012 MCB. Added as a reference (reference_review MEDIUM/VERIFIED) and as verbatim supported_by ("PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding") on the previously interactome-only KEAP1 over-annotation row, giving the demoted antioxidant role a primary citation. |
Both PMIDs fetched/cached via fetch-pmid; every supporting_text is a verbatim substring of the
cached full text (whitespace-normalized, confirmed against the reference validator). One NEW annotation
was added — GO:0031491 nucleosome binding — a correctly-branched MF the review had captured only as
uninformative "protein binding"; it is marked non-core (a chromatin-anchoring/targeting activity, not
the central adaptor function). No existing curation decision was weakened by Affinage's coarse GO layer.
Net assessment
The AIGR review and Affinage agree fully on PALB2's core BRCA1↔BRCA2 adaptor/scaffold and RAD51-loading
HR biology, on intrinsic N-terminal DNA binding stimulating strand invasion, and on demoting the KEAP1,
POLη, and MRG15 roles to non-core. Affinage's own GO mechanism_profile is coarse and in places
wrong-branch (catalytic activity, acting on DNA PALB2 does not possess; histone binding where the
evidence supports nucleosome binding; generic molecular function regulator activity) and was
correctly not imported. Affinage's real value was its dense, well-anchored narrative, which surfaced two
concrete additions incorporated conservatively: (1) a NEW, precise GO:0031491 nucleosome binding
annotation for the ChAM motif (replacing an uninformative "protein binding" row), and (2) the primary
KEAP1-NRF2 paper (PMID:22331464) to ground a secondary role that previously rested only on
high-throughput interactome hits. Over-reaches Affinage narrates (ubiquitin-recruitment cascade, ATM/ATR
phosphoregulation, G2/M checkpoint, transcriptional co-activation, cGAS-STING immune signaling) are
regulation-of / consequence-of / partner functions and were correctly kept out of PALB2's MF/BP set.
File remains ✓ Valid (one benign deep-research-file warning).