PALB2 (Q86YC2) review notes

PALB2 = Partner And Localizer of BRCA2 / FANCN. Human, 1186 aa, chr16. Tumor suppressor;
biallelic loss = Fanconi anemia group N (FANCN); monoallelic = breast/pancreatic/ovarian
cancer predisposition.

Domain architecture (from UniProt Q86YC2)

• N-terminal coiled-coil (res ~9-41): binds BRCA1; also mediates self-oligomerization.
• N-terminal region 1-579: DNA-binding domain (preference D-loop > dsDNA > ssDNA).
• RAD51 interaction region ~101-184 (mapped in PMID:20871616).
• ChAM (chromatin-association motif, ~395-446): intrinsic chromatin/nucleosome binding.
• C-terminal 7-bladed WD40 β-propeller (~853-1186): binds BRCA2 (pocket at WD4/WD5
  crossover), and also RAD51C, RAD51, XRCC3; also required for POLH interaction.

Core biology (verified from cached publications)

• Scaffold/adaptor: PALB2 physically links BRCA1 (coiled-coil) to BRCA2 (WD40), forming the
  BRCA1-PALB2-BRCA2 complex required for HR. PMID:19369211 and PMID:19369211.
• Localizes/stabilizes BRCA2. PMID:16793542.
• WD40 domain binds BRCA2 (structure). PMID:19609323 and structure of "PALB2 carboxy-terminal β-propeller domain in complex with a BRCA2 peptide".
• WD40 also directly binds RAD51C, RAD51, BRCA2, XRCC3; scaffolds an HR complex. PMID:24141787 and PMID:24141787.
• Chromatin association + oligomerization anchor BRCA2·RAD51 at breaks. PMID:19423707 and PMID:19423707.
• DNA binding: N-terminal half binds DNA, D-loop > dsDNA > ssDNA. PMID:20871616.
• Stimulates RAD51 recombinase / D-loop formation, cooperates with RAD51AP1. PMID:20871616 and PMID:20871616.
• N-DBD has intrinsic strand-exchange activity; DNA binding needed for RAD51 foci/HDR. PMID:31017574 and PMID:31017574.
• Strand-exchange/DBD is intrinsically disordered; coiled-coil dimerization + ssDNA-driven tetramerization; scaffold linking BRCA1-BRCA2-RAD51. PMID:39584160 and PMID:39584160.
• With BRCA2 stimulates POLH DNA synthesis at blocked forks. PMID:24485656.
• Part of an ERCC5/XPG-BRCA2-PALB2-DSS1-RAD51 HR complex. PMID:26833090.
• BRCA1-PALB2 interaction directs HR vs SSA choice. PMID:28398198 and PMID:28319063.
• MRG15/MORF4L1 binds PALB2 (chromatin targeting). PMID:20332121.

Review decisions summary

• Core molecular function best captured as molecular adaptor activity (GO:0060090):
  PALB2 bridges BRCA1 and BRCA2 (and scaffolds RAD51C/RAD51/XRCC3) for HR. Uninformative
  "protein binding" (GO:0005515) IPI rows to BRCA1/BRCA2 MODIFIED -> GO:0060090; the many
  other IPI rows (RAD51, RAD51C, XRCC3, RAD51AP1, MORF4L1, POLH, KEAP1, XPG, high-throughput
  interactome papers) MARKED_AS_OVER_ANNOTATED (real interactions but uninformative term;
  informative role captured in core_functions).
• Genuine DNA binding (GO:0003677), ssDNA binding (GO:0003697), homodimerization
  (GO:0042803), homotetramerization (GO:0051289) accepted (experimental).
• HR (GO:0000724) accepted across IBA/IEA/IDA/IMP. Nucleoplasm/nucleus accepted; nuclear
  speck (HPA IDA) kept as non-core.
• KEAP1 interaction (KEAP1-NRF2 oxidative-stress) is a secondary role, not the HR-scaffold
  core function; over-annotated as protein binding.