FANCD2 (Q9BXW9) review notes

Summary of biology

FANCD2 (Fanconi anemia group D2 protein; 1451 aa) is the central effector of the Fanconi
anemia (FA)/BRCA DNA interstrand crosslink (ICL) repair pathway. With its paralog FANCI it
forms the ID2 heterodimer. Upon replication stress/ICLs, FANCD2 is monoubiquitinated at
Lys561 by the FA core complex (E3 = FANCL, E2 = UBE2T), which converts the open ID2 trough
into a closed sliding DNA clamp that encircles duplex DNA, loading ID2 onto chromatin to
coordinate nucleolytic incision (unhooking), translesion synthesis (POLN) and homologous
recombination. It is deubiquitinated by the USP1–UAF1(WDR48) complex. FANCD2 also protects
stalled replication forks, restrains nucleases, and localizes to common fragile sites /
ultrafine anaphase bridges (with BLM). Loss causes Fanconi anemia complementation group D2:
bone marrow failure, congenital malformations, chromosomal instability, MMC/DEB
hypersensitivity, cancer predisposition.

Key provenance (verbatim)

• ID2 clamp / monoubiquitination function:
  PMID:32269332
  PMID:32269332
  PMID:32269332

• Replication-coupled ICL repair, incision + TLS:
  PMID:19965384

• ssDNA binding / ring-like particle:
  PMID:19609304
  PMID:19609304

• FANCI as monoubiquitinated paralog / partner:
  PMID:17460694

• BRCA2 direct interaction (HR):
  PMID:15115758
  PMID:18212739

• FAN1 nuclease recruitment by monoubiquitinated FANCD2:
  PMID:20603015

• POLN interaction (crosslink repair / HR):
  PMID:19995904

• UHRF1/UHRF2 promote FANCD2 recruitment/monoubiquitination (nucleus/chromatin):
  PMID:30335751
  PMID:30335751

• MEN1/menin interaction; enhanced by gamma-irradiation:
  PMID:12874027

• CEBPD/IPO4 nuclear import:
  PMID:20805509

• Monoubiquitination at Lys561 by FANCL/UBE2T; DUB USP1; chromatin binding requirement
  (UniProt Q9BXW9 PTM/SUBUNIT sections).

Curation decisions (high level)

• Core: interstrand cross-link repair (GO:0036297); ssDNA/damaged DNA binding (clamp);
  DNA-repair (ID2) complex; nuclear/chromatin localization; HR-mediated DSB repair.
• protein binding (GO:0005515, 11 IPI rows): REMOVE — uninformative MF; the underlying
  interactions (FANCI, BRCA2, MEN1, MRE11/NBS1, FAN1, CEBPD, EGFR) are recorded here/in
  more specific terms.
• DNA polymerase binding (GO:0070182, IBA + POLN IPI): KEEP_AS_NON_CORE — real but peripheral.
• Meiotic terms (GO:0007129, GO:1990918): KEEP_AS_NON_CORE (germline-restricted, IBA).
• nucleolus (GO:0005730), response to gamma radiation (GO:0010332): KEEP_AS_NON_CORE.
• Added NEW GO:0003697 single-stranded DNA binding (IDA, PMID:19609304).