Affinage

FANCI

Fanconi anemia group I protein · UniProt Q9NVI1

Length
1328 aa
Mass
149.3 kDa
Annotated
2026-06-09
78 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FANCI is a central effector of the Fanconi anemia DNA interstrand crosslink (ICL) repair pathway, functioning as the obligate partner of FANCD2 in a heterodimeric (ID2) clamp that recognizes and processes damaged replication forks (PMID:17412408, PMID:17460694). The complex acts as a sliding clamp that diffuses on dsDNA and stalls specifically at single-strand/double-strand junctions characteristic of stalled forks, then encircles the DNA through a closed conformation (PMID:39085614, PMID:32066963). Activation proceeds through ordered post-translational regulation: ATR phosphorylates conserved S/TQ motifs (notably S556, S559, S565), priming the complex by destabilizing its open state, stabilizing DNA and FANCD2 association, and protecting the eventual ubiquitin marks from USP1:UAF1 (PMID:18931676, PMID:32117957, PMID:36050501), and PP2A dephosphorylates an inhibitory FANCD2 cluster to license chromatin loading (PMID:39535917). The UBE2T-FANCL E2-E3 pair then monoubiquitinates FANCD2 (K561) and FANCI (K523), a reaction strongly stimulated by FANCI's DNA binding and required for clamping the heterodimer on dsDNA (PMID:19111657, PMID:19589784, PMID:22287633, PMID:32167469); FANCI's own ubiquitin reciprocally protects FANCD2's ubiquitin from USP1-UAF1 deubiquitination and enables re-ubiquitination, establishing an interdependent ubiquitin lock (PMID:32510829, PMID:36385258). The activated clamp recruits the downstream nuclease FAN1 and directly stabilizes RAD51-DNA filaments to protect fork ends (PMID:20671156, PMID:27694619). Beyond canonical repair, FANCI carries out FANCD2-independent functions: it restrains dormant origin firing under replication stress (PMID:25843623), localizes to the nucleolus to support pre-rRNA transcription and large-subunit processing in its deubiquitinated state (PMID:30692263), stimulates homologous recombination D-loop formation and is essential for meiosis and spermatogenesis (PMID:31219578, PMID:34373449), and can switch from FANCD2 partnering to PIDD1 binding to drive caspase-2/PIDDosome-dependent apoptosis when ICL repair fails (PMID:34256011). Patient-derived mutations affecting the C-terminal NLS/EDGE region and the Tower domain disrupt these activities, linking FANCI to the Fanconi anemia phenotype (PMID:20971953, PMID:27405460).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2007 High

    Establishing that FANCI is a damage-induced, monoubiquitinated partner of FANCD2 defined the ID complex as the activated effector module of the FA pathway.

    Evidence Reciprocal Co-IP, chromatin fractionation, and patient cell complementation, with MS phosphoproteomics identifying FANCI as an ATM/ATR substrate

    PMID:17412408 PMID:17460694

    Open questions at the time
    • Mechanism by which the two ubiquitin marks maintain each other was not structurally defined
    • DNA substrate specificity not yet established
  2. 2008 High

    Showing that S/TQ phosphorylation acts as a molecular switch and that FANCI directs FANCL-mediated FANCD2 ubiquitination to the correct lysine established the activation logic of the pathway.

    Evidence Alanine/phosphomimetic mutagenesis with DT40 complementation and in vitro reconstituted ubiquitination with purified UBE2T-FANCL-FANCI

    PMID:18931676 PMID:19111657

    Open questions at the time
    • Which kinase acts at which site and the temporal order were not resolved
    • Structural basis of phospho-activation unknown
  3. 2009 High

    Defining direct, branched-DNA-preferring binding by FANCI and the precise K523 acceptor lysine connected FANCI's DNA recognition to its biochemical activation.

    Evidence EMSA and Co-IP with purified recombinant proteins, truncation/point-mutant mapping, and in vitro ubiquitination identifying K523

    PMID:19561358 PMID:19589784

    Open questions at the time
    • How DNA binding feeds into ubiquitination stimulation not yet mechanistically linked
    • In vivo relevance of branched-DNA preference untested
  4. 2010 High

    Identifying FAN1 recruitment as strictly dependent on ID complex monoubiquitination connected the activated clamp to a downstream repair nuclease, and ortholog studies confirmed pathway conservation.

    Evidence Co-IP, epistatic knockdown, and foci assays in human cells; RNAi epistasis in C. elegans; C-terminal NLS/EDGE mutant complementation

    PMID:20075016 PMID:20671156 PMID:20971953

    Open questions at the time
    • How ubiquitin recruits FAN1 mechanistically not defined
    • Functional separability of NLS versus EDGE elements partially resolved
  5. 2011 High

    The first crystal structure of the ID complex mapped ubiquitination and phosphorylation sites to the I-D interface and revealed DNA-binding surfaces, providing the structural framework for regulated DNA engagement.

    Evidence X-ray crystallography (3.4 Å ID complex; FANCI-DNA electron density) with in vitro DNA binding; RAD18 Co-IP/KO defining an upstream ligase requirement

    PMID:21355096 PMID:21764741

    Open questions at the time
    • Conformational changes upon ubiquitination not captured
    • Mechanism of RAD18 contribution to ID loading incompletely defined
  6. 2012 Medium

    DNA-dependent stimulation of FANCD2 ubiquitination, FANCI's role in nucleosome assembly, and phosphorylation-triggered ID dissociation refined the model of how DNA and modifications gate complex activity.

    Evidence In vitro reconstituted ubiquitination with defined DNA substrates and DNA-binding mutants, nucleosome assembly assays, and Co-IP with phosphomutants

    PMID:22287633 PMID:22753026 PMID:22828868

    Open questions at the time
    • Whether ID dissociation versus clamping is the activating step was unresolved at this stage
    • Histone chaperone role of FANCI is stimulatory, not direct
  7. 2014 High

    Demonstrating that FANCI DNA binding is required for DNA-stimulated FANCD2 ubiquitination within ID2, while DNA stimulates FANCI ubiquitination FANCL-independently in FANCD2's absence, dissected the differential roles of the two subunits.

    Evidence In vitro reconstitution with purified human FANCD2/FANCI/UBE2T/FANCL, multiple DNA substrates, and DNA-binding mutants

    PMID:24623813

    Open questions at the time
    • Physiological significance of FANCL-independent FANCI ubiquitination unclear
    • Single-lab biochemistry
  8. 2015 High

    Defining FANCD2-independent roles—restraint of dormant origin firing and a requirement for FA core complex recruitment—established FANCI as more than a passive FANCD2 partner.

    Evidence STORM super-resolution imaging, DNA fiber assays, phosphomutants, and foci assays with ATR inhibition and USP1 depletion

    PMID:25843623 PMID:26430909

    Open questions at the time
    • Molecular mechanism by which FANCI restrains origin firing not defined
    • How deubiquitinated FANCI promotes core complex recruitment unknown
  9. 2016 High

    Cryo-EM of the unmodified complex, demonstration of RAD51 filament stabilization, mapping of the dimeric FANCL catalytic module, and discovery of Akt regulation expanded both the structural and signaling reach of FANCI.

    Evidence Cryo-EM with recruitment assays and patient mutations, purified-protein RAD51/nuclease assays, EM/crosslink-MS of the core complex, and Co-IP/phospho-Akt assays

    PMID:27097374 PMID:27405460 PMID:27694619 PMID:27986592

    Open questions at the time
    • Akt/PHLPP1 regulation rests on single-method Co-IP/knockdown evidence
    • Core complex catalytic module model lacked mutagenesis validation
  10. 2017 Medium

    Resolving two temporally distinct phosphorylation phases (ubiquitination-independent S556 versus ubiquitination-linked S559/S565) and identifying spliceosome (SF3B1) association revealed layered regulation and RNA-related roles.

    Evidence Phospho-specific antibodies, USP1 depletion, phosphomutant complementation, ICL repair assays; Co-IP, PLA, and chromatin fractionation for SF3B1

    PMID:28636932 PMID:29030393

    Open questions at the time
    • Kinase responsible for each phosphorylation phase not fully assigned
    • Direct versus indirect role in splicing factor dynamics unclear
  11. 2019 Medium

    Defining nucleolar/rRNA functions, ssRNA/R-loop binding, and direct HR D-loop stimulation broadened FANCI's repertoire into RNA metabolism and FANCD2-independent recombination.

    Evidence Nucleolar IF with rRNA labeling and USP1/USP36 perturbation, EMSA/ubiquitination with RNA and R-loop substrates, and D-loop assays with KO mouse phenotypes; plus CTDP1 Co-IP

    PMID:30650351 PMID:30692263 PMID:31219578 PMID:31240132

    Open questions at the time
    • Mechanistic role of FANCI in pre-rRNA processing not defined
    • How RNA/R-loop binding integrates with ICL repair unknown
  12. 2020 High

    A series of cryo-EM and reconstitution studies established the ubiquitin-clamping mechanism: monoubiquitination converts the open ID complex into a closed clamp encircling dsDNA, with FANCI's ubiquitin protecting FANCD2's mark from USP1-UAF1, and ATR phosphorylation reinforcing this lock.

    Evidence Cryo-EM of modified complexes, in vitro clamping/EMSA and EM filament assays, deubiquitination assays with ubiquitin-surface mutants, and ATR reconstitution

    PMID:32066963 PMID:32117957 PMID:32167469 PMID:32510829

    Open questions at the time
    • How the clamp transitions to recruiting downstream factors not structurally captured
    • Mechanism converting clamping into productive repair incomplete
  13. 2021 High

    Discovery of a FANCD2-versus-PIDD1 partner switch and an essential meiotic role established FANCI as a decision point between repair and apoptosis and a germline-critical factor.

    Evidence Reciprocal Co-IP, caspase-2 activation, genetic epistasis with nuclease deletions and ubiquitination-resistant mutants; Fanci KO mouse with meiotic/epigenetic readouts

    PMID:34256011 PMID:34373449

    Open questions at the time
    • Signal that triggers the partner switch upon repair failure not defined
    • Mechanism linking FANCI to meiotic histone methylation unclear
  14. 2022 High

    Phosphomimetic and IUbD2 cryo-EM structures revealed how phosphorylation primes closure independent of the core complex and how the two subunits' ubiquitinations are mechanistically interdependent.

    Evidence Cryo-EM of phosphomimetic and FANCI-ubiquitinated complexes with reconstituted ubiquitination/deubiquitination assays

    PMID:36050501 PMID:36385258

    Open questions at the time
    • Coupling of phospho-priming to the in vivo kinase cascade not addressed
    • Single-lab structural studies
  15. 2024 High

    Single-molecule and cryo-EM evidence unified the model as a sliding clamp that stalls at ss-dsDNA junctions, while PP2A licensing, R-loop/SRSF1 functions, open-chromatin engagement, and PARP1 regulation extended FANCI into broader genome maintenance and therapeutic contexts.

    Evidence TIRF single-molecule imaging and cryo-EM of D2-I on DNA; reconstituted PP2A dephosphorylation-ubiquitination; Co-IP/mRNA export/R-loop assays; ATAC/ChIP-seq; PARP1 Co-IP and PARP-inhibitor sensitivity

    PMID:38165804 PMID:39037758 PMID:39085614 PMID:39535917 PMID:41505257

    Open questions at the time
    • PARP1 regulation by FANCI rests on limited mechanistic evidence
    • How fork-junction surveillance integrates with downstream nuclease choice not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FANCI's diverse FANCD2-independent activities (origin firing, nucleolar rRNA processing, RNA/R-loop metabolism, apoptotic switching) are coordinately regulated and prioritized within a single cell remains unresolved.
  • No unified model integrating canonical ICL repair with non-canonical functions
  • Determinants of partner choice (FANCD2 vs PIDD1 vs others) across stress contexts unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 7 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2 GO:0005730 nucleolus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-73894 DNA Repair 4 R-HSA-1474165 Reproduction 2 R-HSA-69306 DNA Replication 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-5357801 Programmed Cell Death 1
Partners
FAN1FANCD2FANCLPHLPP1PIDD1RAD51UBE2TUSP1
Complex memberships
FA core complexFANCI-FANCD2 (ID2) complexPIDDosome (PIDD1-RAIDD-caspase-2)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 FANCI is monoubiquitinated (on K523) and forms the FANCI-FANCD2 (ID) complex that localizes to chromatin in response to DNA damage; ubiquitination of each protein is required for maintenance of ubiquitin on the other, indicating a dual ubiquitin-locking mechanism. Co-immunoprecipitation, western blot, chromatin fractionation, siRNA knockdown, patient cell complementation Cell High 17412408 17460694
2007 FANCI is an ATM/ATR kinase substrate required for resistance to mitomycin C-induced DNA interstrand crosslinks; it is a paralog of FANCD2 likely evolving from a common ancestral gene. Mass spectrometry phosphoproteomics, siRNA knockdown, MMC sensitivity assay Cell High 17412408
2008 Multiple phosphorylation of conserved Ser/Thr-Gln (S/TQ) motifs in FANCI acts as a molecular switch to activate the FA pathway: alanine substitutions at six clustered S/TQ sites abrogate monoubiquitination and focus formation of both FANCI and FANCD2, while phosphomimetic mutations constitutively activate monoubiquitination and confer crosslink resistance. Site-directed mutagenesis (alanine and phosphomimetic substitutions), chicken DT40 cell complementation, MMC sensitivity assay, immunofluorescence Nature structural & molecular biology High 18931676
2008 FANCI enhances FANCD2 monoubiquitination by Ube2t-FANCL in vitro and restricts ubiquitination to the correct in vivo lysine residue on FANCD2. In vitro reconstituted ubiquitination assay with purified Ube2t, FANCL, and FANCI proteins Molecular cell High 19111657
2009 FANCI directly binds DNA with a preference for branched structures; the DNA-binding domain spans approximately residues 200–1000; the FANCI-FANCD2 complex shows enhanced and preferential binding to branched DNA substrates compared to either protein alone; FANCI interacts with FANCD2 through its C-terminal region (residues 1001–1328). Purified recombinant protein DNA-binding assays (EMSA), co-immunoprecipitation with purified proteins, truncation and point mutant analysis, immunofluorescence The Journal of biological chemistry High 19561358 19589784
2009 FANCI is monoubiquitinated specifically on Lys-523 by the UBE2T-FANCL E2-E3 pair in vitro. In vitro ubiquitination assay with purified recombinant proteins The Journal of biological chemistry High 19589784
2010 The monoubiquitinated FANCI-FANCD2 (ID) complex recruits the downstream nuclease FAN1 to sites of DNA damage to facilitate ICL repair; FAN1 accumulation is strictly dependent on ID complex monoubiquitination. Co-immunoprecipitation, siRNA knockdown, immunofluorescence foci assay, ICL sensitivity assay Science High 20671156
2011 Crystal structure of the ~300 kDa FANCI-FANCD2 (ID) complex at 3.4 Å reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface; electron density maps of FANCI-DNA crystals show binding sites for both single- and double-stranded DNA, suggesting the ID complex recognizes DNA structures formed at replication fork-ICL encounters. X-ray crystallography (3.4 Å crystal structure of ID complex; 7.8 Å electron density of FANCI-DNA), in vitro DNA binding assays Science High 21764741
2012 FANCI stimulates FANCD2-mediated nucleosome assembly (histone chaperone activity) in vitro, although FANCI alone lacks nucleosome-assembly activity; this activity is required for DNA crosslink repair. In vitro nucleosome assembly assay, histone H3 mobility assay in FANCD2-knockdown cells, cisplatin survival assay with assembly-defective FANCD2 mutants The EMBO journal Medium 22828868
2012 Various forms of DNA (ssDNA, dsDNA, branched DNA) robustly stimulate FANCD2 monoubiquitination in vitro in a manner strictly requiring FANCI; a FANCI mutant defective in DNA binding is also defective in stimulating FANCD2 monoubiquitination. In vitro reconstituted ubiquitination assay with purified components and defined DNA substrates; FANCI DNA-binding mutants Nucleic acids research High 22287633
2012 FANCI phosphorylation (at S/TQ sites) is the molecular trigger for FANCD2-FANCI dissociation: phosphodead FANCI fails to dissociate from FANCD2, while phosphomimetic FANCI cannot interact with FANCD2; FANCD2-FANCI complex represents the inactive form and dissociates upon DNA damage-induced FA pathway activation. Co-immunoprecipitation, phosphomimetic and phosphodead FANCI mutant expression, chromatin fractionation, flow cytometry cell-cycle analysis Nucleic acids research Medium 22753026
2014 FANCI DNA-binding activity is required for DNA-stimulated FANCD2 monoubiquitination within the ID2 complex; duplex or branched DNA strongly stimulates FANCD2 monoubiquitination in the ID2 complex via FANCL interaction, but in the absence of FANCD2, DNA stimulates FANCI monoubiquitination in a FANCL-independent manner. In vitro reconstituted ubiquitination assay with purified human FANCD2, FANCI, UBE2T, FANCL and defined DNA substrates; FANCI DNA-binding mutants Nucleic acids research High 24623813
2015 ATR-mediated phosphorylation of FANCI inhibits dormant origin firing while promoting replication fork restart/DNA repair; FANCI co-localizes with MCM-bound chromatin under replication stress; cells lacking FANCI have reduced origins and increased inter-origin distances. Super-resolution microscopy (STORM), DNA fiber assay, phosphomimetic/phosphodead FANCI mutants, siRNA knockdown Molecular cell High 25843623
2015 FANCI, but not its partner FANCD2, is required for efficient FA core complex recruitment to sites of DNA damage (nuclear foci formation); FANCI deubiquitination by USP1 is required for this function; monoubiquitination and ATR-dependent phosphorylation of FANCI are not required for core complex recruitment. Immunofluorescence foci assay, ATR inhibition, USP1 depletion, FANCI mutant complementation in isogenic cell lines PLoS genetics Medium 26430909
2016 The FANCI-FANCD2 (I-D) complex directly binds RAD51 and stabilizes RAD51-DNA filaments; DNA binding activity of FANCI (but not FANCD2) is required for this stabilization; the stabilized RAD51 filament protects DNA ends from FAN1 nucleolytic degradation. Pulldown assay with purified proteins, RAD51-DNA filament stabilization assay, nuclease protection assay, FANCI DNA-binding mutants Nucleic acids research High 27694619
2016 The FA core complex contains a homo-dimeric catalytic module (FANCB-FANCL-FAAP100 dimer of trimers) with two FANCL molecules positioned to ubiquitinate both FANCI and FANCD2; FANCC-FANCE-FANCF bridges the catalytic module to FANCI-FANCD2 and stabilizes the dimerization interface. Structural electron microscopy combined with crosslink-coupled mass spectrometry Cell reports Medium 27986592
2016 FANCI acts as a negative regulator of Akt activation: depletion of FANCI (but not FANCD2 or USP1) results in increased Akt phosphorylation/activation due to reduced PHLPP1-Akt interaction; FANCI forms a complex with Akt, PHLPP1, PHLPP2, FANCD2, USP1, and UAF1. Co-immunoprecipitation, siRNA knockdown, phospho-Akt western blot, apoptosis assay Cell cycle Medium 27097374
2016 Cryo-EM structure of the human FANCD2-FANCI complex reveals an inner cavity large enough to accommodate dsDNA and a protruding Tower domain; the complex is recruited to a stalled replication fork before monoubiquitination, and this recruitment triggers the activating monoubiquitination event; disease-causing mutations in the Tower domain impair this function. Cryo-EM structure determination, recruitment assay at defined ICL substrates, patient mutation analysis Nature communications High 27405460
2017 FANCI phosphorylation at S/TQ sites occurs in two temporally distinct phases: serine 556 is phosphorylated upstream of monoubiquitination (ubiquitination-independent), while serines 559 and 565 are phosphorylated downstream (ubiquitination-linked); ubiquitination-linked phosphorylation inhibits FANCD2 deubiquitination by USP1 and is required for effective ICL repair. Phospho-specific antibodies against S556, S559, S565; USP1 depletion; phosphomimetic/phosphodead mutant complementation; ICL repair assay Cell reports Medium 28636932
2017 FANCI and FANCD2 associate with spliceosomal protein SF3B1 (U2 snRNP); replication stress induces ATR-dependent release of SF3B1 from nuclear speckles requiring FANCI; chromatin-bound FANCI and FANCD2 prevent accumulation of post-catalytic intron lariats and contribute to eviction of splicing factors. Co-immunoprecipitation, immunofluorescence, chromatin fractionation, proximity ligation assay, siRNA knockdown The Journal of cell biology Medium 29030393
2019 FANCI localizes to the nucleolus and functions in pre-rRNA transcription and large ribosomal subunit pre-rRNA processing independently of FANCD2; in the nucleolus FANCI is predominantly in the deubiquitinated state, requiring both nucleoplasmic deubiquitinase USP1 and nucleolar deubiquitinase USP36. Immunofluorescence (nucleolar localization), RNA metabolic labeling (pre-rRNA processing), siRNA knockdown, USP1/USP36 inhibition/knockdown Proceedings of the National Academy of Sciences Medium 30692263
2019 Purified human FANCI-FANCD2 (ID2) complex binds single-stranded RNA (ssRNA) and R-loop substrates with high affinity, preferring guanine-rich sequences; R-loop binding is via the displaced ssDNA and ssRNA but not the RNA:DNA hybrid; RNA and R-loop substrates strongly stimulate ID2 monoubiquitination in vitro. Electrophoretic mobility shift assay (EMSA), in vitro ubiquitination assay with purified components, R-loop immunofluorescence (DART assay) Cell reports High 30650351
2020 Cryo-EM structures show that monoubiquitinated FANCD2-FANCI adopts a closed conformation that encircles dsDNA; ubiquitin at the FANCD2-FANCI interface acts as a covalent molecular pin to trap the complex on DNA; unmodified isolated FANCD2 forms a homodimer unable to bind DNA, suggesting an autoinhibitory mechanism. Cryo-EM structure determination of recombinant chicken FANCD2-FANCI complexes, DNA binding assays Nature structural & molecular biology High 32066963
2020 Monoubiquitination of FANCI:FANCD2 clamps the heterodimer onto dsDNA, forming filament-like arrays on long dsDNA; clamping requires monoubiquitination of only the FANCD2 subunit; monoubiquitination does not promote specific exogenous protein-protein interactions. In vitro reconstitution of FA pathway with purified components, electron microscopy of FANCI:FANCD2-DNA complexes, EMSA eLife High 32167469
2020 Ubiquitination of FANCD2 promotes a large-scale conformational change in the ID2 complex that increases affinity for dsDNA by forming a secondary 'Arm' interface that encircles DNA; ubiquitination of FANCI protects the ubiquitin on FANCD2 from USP1-UAF1 deubiquitination via key hydrophobic residues on FANCI's ubiquitin. Cryo-EM, biochemical ubiquitination/deubiquitination assays, mutagenesis of ubiquitin hydrophobic surface EMBO reports High 32510829
2020 ATR directly phosphorylates FANCI on serines 556, 559, and 565 to stabilize its association with DNA and FANCD2; this phosphorylation stimulates ubiquitin conjugation to both FANCI and FANCD2 and inhibits deubiquitination by USP1:UAF1; S559 and S565 are particularly important for protecting the complex from USP1:UAF1. In vitro reconstitution with recombinant ATR, FANCI phosphomimetic/phosphodead mutants, deubiquitination assay with USP1:UAF1 Frontiers in cell and developmental biology High 32117957
2021 FANCI switches between two mutually exclusive binding partners depending on ICL repair status: it binds FANCD2 for repair, or alternatively binds PIDD1 to enable PIDDosome (PIDD1-RAIDD-caspase-2) formation and apoptosis when ICL repair fails; monoubiquitination and deubiquitination at K523 regulate interactor selection. Co-immunoprecipitation, caspase-2 activation assay, genetic epistasis with endonuclease deletions, ubiquitination-resistant FANCI mutants Developmental cell High 34256011
2021 FANCI is essential for spermatogenesis in mice: FANCI deletion causes massive germ cell apoptosis, loss of undifferentiated spermatogonia, and impairs FANCD2 foci formation; FANCI is required for H3K4 and H3K9 methylation on meiotic sex chromosomes. Fanci knockout mouse model, immunofluorescence, histone methylation analysis, germ cell apoptosis assay Cell death & disease Medium 34373449
2019 FANCI interacts with RAD51 and stimulates D-loop formation (homologous recombination) independently of FANCD2; FANCI co-localizes with RPA along meiotic chromosomes; Fanci knockout mice display severe hypogonadism and meiotic phenotype. Fanci conditional knockout mouse, D-loop assay with purified proteins, immunofluorescence on meiotic chromosomes, co-immunoprecipitation Nucleic acids research Medium 31219578
2022 Cryo-EM structures of phosphomimetic FANCI-FANCD2 show that phosphorylation destabilizes the open state of the complex and promotes closure around DNA independent of the FA core complex; phosphomimetic mutations do not substantially alter DNA binding affinity but alter conformational dynamics to prime the complex for ubiquitination. Cryo-EM structure determination of phosphomimetic FANCI-FANCD2, biochemical ubiquitination assays, EMSA Nature structural & molecular biology High 36050501
2022 Cryo-EM structure of the FANCI-ubiquitinated/FANCD2-unmodified (IUbD2) complex shows the complex in the closed DNA-clamping conformation; FANCD2 target lysine K561 becomes fully exposed (primed for ubiquitination) in IUbD2-DNA, while FANCI's K523 is primed for ubiquitination in ID2Ub-DNA; FANCI ubiquitination maintains FANCD2 ubiquitination by preventing its deubiquitination and enabling re-ubiquitination. Cryo-EM structure determination (4.1 Å), in vitro deubiquitination assay with USP1-UAF1, reconstituted ubiquitination assays The EMBO journal High 36385258
2024 FANCD2-FANCI is a sliding clamp that diffuses on dsDNA and stalls at ss-dsDNA junctions (structures formed at stalled replication forks); cryo-EM structures show that stalled D2-I makes specific contacts with the ss-dsDNA junction distinct from those of sliding D2-I, providing a unified mechanism for surveillance and recognition of stalled replication forks. Single-molecule imaging (total internal reflection fluorescence microscopy), cryo-EM structure determination of D2-I on DNA substrates Nature High 39085614
2024 PP2A phosphatase complex dephosphorylates an inhibitory cluster in FANCD2, licensing FANCD2/FANCI complex loading onto chromosomes and enabling monoubiquitination; this was reconstituted in vitro as a coupled dephosphorylation-ubiquitination reaction. In vitro reconstitution of coupled dephosphorylation-ubiquitination reaction with purified PP2A, super-resolution live-cell single-molecule tracking, genetic epistasis with PP2A depletion Cell reports High 39535917
2024 SRSF1 physically interacts with FANCD2 and acts together to suppress R-loop formation via mRNA export regulation; SRSF1 stimulates FANCD2 monoubiquitination in an RNA-dependent fashion; FANCD2 monoubiquitination is required for assembly of the SRSF1-NXF1 nuclear export complex and mRNA export. Co-immunoprecipitation, mRNA export assay, R-loop immunofluorescence, FANCD2 monoubiquitination assay, cancer-associated SRSF1 mutants Cell reports Medium 38165804
2024 The FANCD2-FANCI heterodimer dynamically interacts with open chromatin regions including DSB-induced open chromatin; loaded FANCD2-FANCI stabilizes open chromatin and promotes DNA resection and RPA loading through increased BRCA1 and BLM association; chromatin-loaded FANCD2-FANCI promotes G2 cell cycle arrest via the ATR-CHK1-WEE1 axis. ATAC-seq, ChIP-seq, immunofluorescence, genetic epistasis with ATM/ATR/FA core complex perturbations, flow cytometry cell cycle assay Cell reports Medium 41505257
2010 In C. elegans, FANCI homolog is required for FANCD2 focus formation and ubiquitination after DNA crosslinking; FANCM, FANCI, and checkpoint proteins RPA, ATR, and CHK1 are all required for FANCD2 activation, demonstrating conservation of the FANCD2 activation pathway involving FANCI. RNAi knockdown, immunofluorescence foci assay, ubiquitination assay in C. elegans DNA repair Medium 20075016
2011 RAD18 E3 ubiquitin ligase binds FANCD2 and is required for efficient monoubiquitination and chromatin localization of both FANCD2 and FANCI; mutation of the RAD18 RING domain ablates interaction with and chromatin loading of FANCD2; FANCD2 ubiquitination is normal in cells with ubiquitination-resistant PCNA. Co-immunoprecipitation, RAD18 knockout cells, RING domain mutants, chromatin fractionation, MMC sensitivity assay Blood Medium 21355096
2013 FANCI is dispensable for FANCD2-dependent BLM complex regulation: FANCD2 (but not FANCI) maintains BLM stability, is required for complete BLMcx assembly, recruits BLMcx to replicating chromatin, and mediates BLMcx phosphorylation in response to DNA damage, demonstrating functional separation of the two ID complex partners. Co-immunoprecipitation, siRNA knockdown, chromatin fractionation, DNA fiber assay, BLM stability assay Nucleic acids research Medium 23658231
2010 The C-terminus of FANCI (last 30 residues) contains two separable functional elements: a nuclear localization signal required for nuclear import of FANCI and robust FANCD2 monoubiquitination, and an EDGE motif important for DNA crosslink repair; the patient-derived R1299X mutation deletes both elements causing protein mislocalization. Patient-derived mutant complementation, nuclear fractionation, monoubiquitination assay, ICL sensitivity assay, site-directed mutagenesis Blood Medium 20971953
2019 FANCI directly binds IMPDH2 and prevents its degradation; this interaction activates MEK/ERK/MMP signaling in lung adenocarcinoma cells; FANCI knockdown inhibits proliferation, migration, and invasion which can be reversed by IMPDH2 overexpression. Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, rescue by IMPDH2 overexpression, xenograft OncoTargets and therapy Low 32021289
2019 CTDP1 interacts with FANCI (via CTDP1's BRCT domain) and regulates FANCI chromatin localization, γ-H2AX interaction, and S/TQ motif phosphorylations; CTDP1 expression promotes FANCA and FANCD2 foci formation and enhances homologous recombination repair efficiency. Co-immunoprecipitation, chromatin fractionation, phospho-FANCI western blot, HR repair assay, siRNA knockdown Cell death discovery Medium 31240132
2018 BRMS1 directly interacts with FANCI (via its linker region between two coiled-coil motifs) and is required for efficient monoubiquitination of both FANCI and FANCD2 in response to ICL damage; BRMS1-deficient cells show suppressed FANCD2 foci formation and ICL hypersensitivity. Co-immunoprecipitation with domain mapping, BRMS1 knockout/knockdown, monoubiquitination assay, FANCD2 foci assay, ICL sensitivity assay Oncology reports Medium 30365131
2024 FANCI interacts with PARP1 and suppresses its nuclear localization and functionality; FANCI inhibition sensitizes breast cancer cells to PARP inhibitor talazoparib in the absence of BRCA mutations. Co-immunoprecipitation, immunofluorescence (PARP1 nuclear localization), FANCI siRNA knockdown, PARP inhibitor sensitivity assay Cancer research Low 39037758

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 586 17412408
2007 FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nature structural & molecular biology 233 17460694
2010 FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science (New York, N.Y.) 209 20671156
2008 FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nature structural & molecular biology 186 18931676
2008 Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Molecular cell 158 19111657
2015 ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. Molecular cell 130 25843623
2011 Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway. Science (New York, N.Y.) 125 21764741
2015 Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia. Cell reports 114 26119737
2007 Identification of the Fanconi anemia complementation group I gene, FANCI. Cellular oncology : the official journal of the International Society for Cellular Oncology 110 17452773
2020 FANCD2-FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair. Nature structural & molecular biology 99 32066963
2013 FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery. Nucleic acids research 90 23658231
2012 A deletion in the bovine FANCI gene compromises fertility by causing fetal death and brachyspina. PloS one 72 22952632
2009 FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL. The Journal of biological chemistry 72 19589784
2019 Binding of FANCI-FANCD2 Complex to RNA and R-Loops Stimulates Robust FANCD2 Monoubiquitination. Cell reports 71 30650351
2011 The E3 ubiquitin ligase RAD18 regulates ubiquitylation and chromatin loading of FANCD2 and FANCI. Blood 70 21355096
2012 DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI. Nucleic acids research 68 22287633
2014 Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA. Nucleic acids research 66 24623813
2020 Monoubiquitination by the human Fanconi anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays. eLife 65 32167469
2016 The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2. Nature communications 65 27405460
2015 FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2. PLoS genetics 63 26430909
2019 Fanconi anemia protein FANCI functions in ribosome biogenesis. Proceedings of the National Academy of Sciences of the United States of America 55 30692263
2012 Histone chaperone activity of Fanconi anemia proteins, FANCD2 and FANCI, is required for DNA crosslink repair. The EMBO journal 54 22828868
2009 FANCI protein binds to DNA and interacts with FANCD2 to recognize branched structures. The Journal of biological chemistry 53 19561358
2016 The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2. Cell reports 51 27986592
2012 Fanconi anemia proteins FANCD2 and FANCI exhibit different DNA damage responses during S-phase. Nucleic acids research 49 22753026
2021 Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1. Proceedings of the National Academy of Sciences of the United States of America 48 33436409
2016 FANCI-FANCD2 stabilizes the RAD51-DNA complex by binding RAD51 and protects the 5'-DNA end. Nucleic acids research 41 27694619
2019 A Fanci knockout mouse model reveals common and distinct functions for FANCI and FANCD2. Nucleic acids research 38 31219578
2020 Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA. EMBO reports 37 32510829
2017 FANCI and FANCD2 have common as well as independent functions during the cellular replication stress response. Nucleic acids research 34 29059323
2019 Phosphorylation of FANCD2 Inhibits the FANCD2/FANCI Complex and Suppresses the Fanconi Anemia Pathway in the Absence of DNA Damage. Cell reports 31 31167143
2020 ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2. Frontiers in cell and developmental biology 30 32117957
2017 Ubiquitination-Linked Phosphorylation of the FANCI S/TQ Cluster Contributes to Activation of the Fanconi Anemia I/D2 Complex. Cell reports 30 28636932
2024 The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export. Cell reports 29 38165804
2021 Mechanism, specificity, and function of FANCD2-FANCI ubiquitination and deubiquitination. The FEBS journal 29 34137174
2009 Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition. Carcinogenesis 28 19737859
2016 FANCI is a negative regulator of Akt activation. Cell cycle (Georgetown, Tex.) 27 27097374
2015 Novel FANCI mutations in Fanconi anemia with VACTERL association. American journal of medical genetics. Part A 26 26590883
2022 The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination. Nature structural & molecular biology 25 36050501
2016 A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis. Journal of the American Society of Nephrology : JASN 25 27026368
2010 The involvement of FANCM, FANCI, and checkpoint proteins in the interstrand DNA crosslink repair pathway is conserved in C. elegans. DNA repair 24 20075016
2024 FANCD2-FANCI surveys DNA and recognizes double- to single-stranded junctions. Nature 23 39085614
2019 CTDP1 regulates breast cancer survival and DNA repair through BRCT-specific interactions with FANCI. Cell death discovery 22 31240132
2017 Fanconi anemia FANCD2 and FANCI proteins regulate the nuclear dynamics of splicing factors. The Journal of cell biology 22 29030393
2021 FANCI plays an essential role in spermatogenesis and regulates meiotic histone methylation. Cell death & disease 21 34373449
2020 FANCI Cooperates with IMPDH2 to Promote Lung Adenocarcinoma Tumor Growth via a MEK/ERK/MMPs Pathway. OncoTargets and therapy 19 32021289
2021 FANCI functions as a repair/apoptosis switch in response to DNA crosslinks. Developmental cell 17 34256011
2010 Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair. Blood 17 20971953
2015 FANCJ protein is important for the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation. Oncotarget 16 26336824
2020 Structural insight into FANCI-FANCD2 monoubiquitination. Essays in biochemistry 15 32725171
2022 UBE2T regulates FANCI monoubiquitination to promote NSCLC progression by activating EMT. Oncology reports 14 35703356
2021 A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene. Genome medicine 14 34861889
2019 Enzymatic preparation of monoubiquitinated FANCD2 and FANCI proteins. Methods in enzymology 14 30850063
2022 Structural and biochemical basis of interdependent FANCI-FANCD2 ubiquitination. The EMBO journal 13 36385258
2020 Inactivation of ribosomal protein S27-like impairs DNA interstrand cross-link repair by destabilization of FANCD2 and FANCI. Cell death & disease 12 33051438
2013 Coordinate nuclear targeting of the FANCD2 and FANCI proteins via a FANCD2 nuclear localization signal. PloS one 12 24278431
2024 FANCI Inhibition Induces PARP1 Redistribution to Enhance the Efficacy of PARP Inhibitors in Breast Cancer. Cancer research 10 39037758
2022 Silencing of FANCI Promotes DNA Damage and Sensitizes Ovarian Cancer Cells to Carboplatin. Current cancer drug targets 9 35362384
2024 Novel compound heterozygous variants in FANCI cause premature ovarian insufficiency. Human genetics 6 38483614
2023 Molecular Genetic Characteristics of FANCI, a Proposed New Ovarian Cancer Predisposing Gene. Genes 6 36833203
2023 TXNL4B regulates radioresistance by controlling the PRP3-mediated alternative splicing of FANCI. MedComm 6 37168687
2014 Defective FANCI binding by a fanconi anemia-related FANCD2 mutant. PloS one 6 25489943
2023 Fanconi anemia pathway regulation by FANCI in prostate cancer. Frontiers in oncology 5 38023254
2018 BRMS1 participates in regulating cell sensitivity to DNA interstrand crosslink damage by interacting with FANCI. Oncology reports 4 30365131
2014 Expression and purification of human FANCI and FANCD2 using Escherichia coli cells. Protein expression and purification 4 25168188
2025 The long noncoding RNA lnc-FANCI-2 intrinsically restricts RAS signaling in human papillomavirus type 16-infected cervical cancer cells. eLife 3 40878909
2024 PP2A licenses the FANCD2/FANCI complex for chromosome loading. Cell reports 3 39535917
2020 Generation of a human induced pluripotent stem cell line (CMCi001-A) from a patient with karyomegalic interstitial nephritis with homozygous frameshift deletion mutation c.1985_1994del10 of the FANCD2/FANCI-Associated Nuclease 1 gene. Stem cell research 3 32563974
2016 Structural and biophysical properties of h-FANCI ARM repeat protein. Journal of biomolecular structure & dynamics 3 27686023
2025 Expression and clinical significance of FANCI gene in pan-cancer: a comprehensive analysis based on multi-omics data. Frontiers in genetics 2 40417238
2026 Betulinic Acid Suppresses UBE2T Expression via MAPK/ERK Inhibition to Block FANCI and FANCD2 Monoubiquitination in Glioblastoma. Journal of cellular and molecular medicine 1 41486508
2025 Knockdown of FANCI suppresses hepatocellular carcinoma development via the PI3K/Akt/GSK-3β pathway. Heliyon 1 40040987
2024 Novel FANCI and RAD54B Variants and the Observed Clinical Outcomes in a Hungarian Melanoma Cohort. International journal of molecular sciences 1 39795882
2026 The FANCD2-FANCI heterodimer coordinates chromatin openness and cell cycle progression throughout DNA double-strand break repair. Cell reports 0 41505257
2026 Possible link between the apparently pathogenic FANCI variant and beneficial effects in sports performance. Frontiers in genetics 0 41732159
2025 FANCI is involved in the malignant progression of glioma cells by regulating the Akt/Bcl-2 signaling pathway. Discover oncology 0 40358883
2024 SSX2IP promotes cell proliferation and migration in breast cancer by regulating FANCI. Cell biology international 0 39533770
2022 Genetic Study of Fanconi Anemia in Infancy Revealed FANCI Mutations and Defective ALDH2 Variant: A Case Report. Journal of pediatric hematology/oncology 0 34310468

Missed literature

Know a paper Affinage missed for FANCI? Flag it for the maintainers and the community.

No submissions yet.