FANCI (Q9NVI1) review notes

Human Fanconi anemia group I protein. HGNC:25568. 1328 aa. Chromosome 15.

Core biology (synthesized)

FANCI is the obligate heterodimeric partner of FANCD2, forming the FANCI-FANCD2
(ID2) complex, the central effector of the Fanconi anemia (FA) DNA-repair pathway.
Both proteins are monoubiquitinated (FANCI on Lys523) by the FANCL/UBE2T ligase
acting downstream of the multi-subunit FA core complex. Monoubiquitination is
mutually interdependent, and FANCI is required to promote FANCD2 monoubiquitination.
The ID2 complex binds and scans dsDNA with preference for branched structures
(Holliday junctions, overhangs, replication forks); upon monoubiquitination it
rearranges into a closed sliding clamp that encircles duplex DNA to coordinate ICL
repair (nucleolytic incision/unhooking, translesion synthesis, homologous
recombination). FANCI phosphorylation by ATR (S/TQ cluster) acts as a molecular
switch turning the pathway on. Disease: Fanconi anemia complementation group I
(biallelic FANCI mutations).

Provenance

• Identity / paralog / monoubiquitination at K523 / FANCD2 interaction:
  PMID:17460694

• ID2 complex required for ICL repair; monoubiquitination essential:
  PMID:32269332
  PMID:32269332

• DNA clamp / encircles DNA:
  PMID:32269332
  PMID:32269332

• DNA binding, preference for branched DNA:
  PMID:32269332

• FANCI required for replication-coupled ICL repair in S phase:
  PMID:19965384
  PMID:19965384

• FANCI phosphorylation = molecular switch that promotes FANCD2 monoubiquitination:
  PMID:18931676
  PMID:18931676

• FANCD2 monoubiquitination targets ID to chromatin:
  PMID:18931676

• FAN1 interaction (FAN1 recruited by monoubiquitinated FANCD2; FANCI co-purifies):
  PMID:20603015

• POLN interaction / role in crosslink repair and HR:
  PMID:19995904

• CTDP1 interaction / regulation of FANCI:
  PMID:31240132

Localization caveats

• Cytoplasm (UniProt SL / IDA PMID:18445686): PMID:18445686 is an EML3-focused
  mitotic-spindle proteomics paper; FANCI is overwhelmingly a nuclear DNA-repair
  protein. Cytoplasmic annotation is at best a minor/incidental pool -> over-annotated.
• Membrane GO:0016020 (HDA PMID:19946888): from a bulk NK-cell membrane-fraction
  mass-spec survey. FANCI has NO transmembrane region (UniProt) and is a soluble
  nuclear protein. The paper itself notes ~60% of identified proteins are NOT
  plausible membrane proteins and are "transiently associated with membranes"
  PMID:19946888
  -> co-purification artifact; REMOVE.

MF gap

GOA export lacks a DNA-binding MF term for FANCI even though UniProt carries the
DNA-binding keyword and DNA binding is FANCI's defining biochemical activity
(branched/duplex DNA binding; clamp). Added GO:0003677 as NEW.