FANCB (FA complementation group B)

2019-02-01   Sylvie van Twest , Andrew Deans 

St Vincents Institute of Medical Research, 9 Princes St, Fitzroy VIC 3065, Australia;;


Atlas Image
Figure 1: Genomic context of FANCB on chromosome (Adapted from NCBI).


FANCB protein is a component of the Fanconi Anemia (FA) core complex needed for DNA repair. Within the core complex, FANCB forms a protein subcomplex with two other proteins, FAAP100, and an E3 RING ligase FANCL (BL100) to monoubiquitinate FANCD2 and FANCI (ID2), a process that is defective in 95% of all FA patients. FA is a rare, genetic cancer pre-disposition syndrome characterized by chromosomal instability and hypersensitivity to DNA crosslinking agents, such as those used in chemotherapy like mitomycin C (MMC) (Kennedy & DAndrea, 2006). FANCB is the only known X-linked FA gene, and mutations account for 1% of FA cases (Alter & Rosenberg, 2013).


Atlas Image
Figure 2: Schematic of FANCB gene. Black represents exons (protein coding regions), white represents introns (non-coding). Adapted from McCauley et al. 2011.


FANCB has 10 exons, and the translation start site is in exon 3 (Meetei et al., 2004).


The FANCB gene undergoes X-inactivation. The mutated FANCB allele is preferentially inactivated in female carriers (so the wild-type allele is expressed), while males with mutations in FANCB get FA (Meetei et al., 2004). FANCB linked FA accounts for 1% of FA cases, and only affects male patients.



The FANCB gene encodes FANCB protein comprised of 859 amino acids, with a molecular mass of 97726 Da. It has a putative C-terminal nuclear localization signal (Meetei et al., 2004).
Atlas Image
Figure 3: The 9 protein core complex associates in 3 distinct subcomplexes: AG20 (FANC A, G, FAAP20), BL100 (FANC B, L, FAAP100), and CEF (FANC C,E,F). Dashed lines indicate groupings of sub-complexes, while triple lines indicate putative direct protein interactions.


Low expression in tissues. Results from Illumina bodyMap2 transcriptome (BioProject: PRJEB2445) of high throughput sequencing of individual and mixture of 16 human tissue RNA showed highest expression in white blood cells (mean RPKM 0.32), testes (mean RPKM 0.23), brain (mean RPKM 0.168), adrenal (mean RPKM 0.164), ovary (mean RPKM 0.153), and lymph nodes (mean PRKM 0.149). Another RNA sequencing project of total RNA from 20 human tissues (BioProject: PRJNA280600) found highest FANCB expression in brain cerebellum (mean RPKM 0.789), and thymus (mean RPKM 0.524). BioProject PRJEB4337 performed HPA RNA sequencing of normal tissues found highest FANCB expression in bone marrow and in lymph nodes. BioProject PRJNA270632 looked at tissue specific FANCB RNA induction during human fetal development from 6 tissues between 10-20 weeks gestational time.


FANCB is a component of the Fanconi Anemia 9 protein "core complex" that acts as a multiunit ubiquitin ligase to ubiquitinate FANCD2 and FANCI in response to DNA damage incurred during DNA replication in S-phase, or to detection of interstand cross links (ICL) (Ceccaldi, Sarangi, & DAndrea, 2016). The key event in the FA pathway is the monoubiquitination of ID2 that activates downstream DNA repair proteins.
The core complex is comprised of 3 separate sub-complexes, , FANCG, FAAP20 (AG20), FANCC, FANCE, FANCF (CEF), and FANCB, FANCL, FAAP100 (BL100) (Huang et al., 2014; Medhurst et al., 2006). The BL100 sub-complex is critical to core complex assembly as it forms a bridge between AG20 and CEF (van Twest et al., 2017). The BL100 subcomplex is dimeric, and FANCB homodimer forms the interface between two copies of FANCL (a RING E3 ligase), and FAAP100 to simultaneously ubiquitinate FANCD2 and FANCI (ID2) (Swuec et al., 2016; van Twest et al., 2017). Correspondingly, FANCB and FAAP100 stabilize FANCL (Rajendra et al., 2014), and enhance its activity by 5-fold in invitro assays (Ling et al., 2007). Mutation in any one of the 19 FA genes results in defective DNA repair.
Atlas Image
Figure 4: Schematic of Fanconi Anemia DNA damage response pathway. In response to interstrand cross links (ICL), or DNA damage from DNA replication, FANCM recruits the 9 protein core complex to DNA damage sites to monoubiquitinate FANC D2 and I. The core complex is comprised of 3 sub-complexes AG20 (FANC A, G, FAAP20), BL100 (FANC B, L, FAAP100), and CEF (FANC C,E,F). Dashed lines indicate groupings of sub-complexes, while triple lines indicate putative direct protein interactions. Within the core complex, FANCL has a RING E3 domain with ubiquitin ligase activity, but mutation in any one of the FA genes leads to defective DNA repair. Ubiquitinated ID2 is activated, and localized to chromatin in nuclear foci to interact with downstream DNA repair proteins (FANCD1, PALB2 (FANCN)) to repair DNA via homologous recombination. Once DNA repair is completed, USP1 deubiquitinates ID2 so that DNA damage response can be reinitiated. Figure adapted from
Atlas Image
Figure 5: FANCB dimer coordinates FANCD2:FANCI monoubiquitination by two FANCL RING-ligases.



Somatic FANCB mutations are very rare, and may occur at normal mutagenesis rate. Small insertions, point mutations, and large deletions have been reported in the FANCB gene (McCauley et al., 2011; Meetei et al., 2004). Most FANCB mutations result in truncation of the encoded protein.

Implicated in

Entity name
Fanconi Anemia
Mutated FANCB is implicated in Fanconi Anemia (FA), a rare genetic condition that results in progressive bone marrow failure (pancytopenia), congenital malformations in 75% of patients (short stature, urogenital defects, café au lait spots, skeletal malformations), and cancer pre-disposition (primarily acute myeloid leukaemia, and certain solid tumours) (Alter, 2014). As the only X-linked FA gene, FANCB accounts for 1% of FA cases, in all other instances FA is autosomal recessive. Mutations in FANCB (and all other core complex FA proteins) is associated with hypersensitivity to DNA-damaging agents, chromosomal instability with increased chromosome breakage and defective DNA repair. In addition to FA, some patients with FANCB mutations also exhibit hydrocephalus-VACTERL (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, and limb anomalies) syndrome. A frameshift FANCB mutation that results in a truncated protein (stop codon at position 446) was associated with VACTERL-H (Holden et al., 2006; McCauley et al., 2011).
The prognosis for FA is poor as there is no cure, and the average lifespan is 20-30 years. If no congenital abnormalities are apparent at birth, patients are often diagnosed with FA when they present with aplastic anemia ages 8-10 (>700 fold risk) (Alter, 2014). Bone marrow transplants are often conducted to correct the haematological issues associated with FA, however due to faulty DNA repair FA patients retain high cancer risk particularly leukaemia, and head and neck squamous cell carcinomas (approximately 500 fold risk) (Shimamura & Alter, 2010).
Diagnostics for FA is done with a chromosomal breakage test; when treated with interstand crosslinking agents such as mitomycin C (MMC) or diepoxybutane (DEB) FA cells exhibit high number chromosomal breakages, and abnormalities as compared to normal cells.


Pubmed IDLast YearTitleAuthors
180246062007Diagnosis, genetics, and management of inherited bone marrow failure syndromes.Alter BP et al
236535792013VACTERL-H Association and Fanconi Anemia.Alter BP et al
271457212016The Fanconi anaemia pathway: new players and new functions.Ceccaldi R et al
42546471971[Early determination of handicaps in the newborn and infants].Frischknecht W et al
166794912006Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome.Holden ST et al
249104282014Modularized functions of the Fanconi anemia core complex.Huang Y et al
168960092006DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes.Kennedy RD et al
173961472007FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway.Ling C et al
219102172011X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations.McCauley J et al
167208392006Evidence for subcomplexes in the Fanconi anemia pathway.Medhurst AL et al
15502821992Ketamine depresses myocardial contractility as evaluated by the preload recruitable stroke work relationship in chronically instrumented dogs with autonomic nervous system blockade.Pagel PS et al
249050072014The genetic and biochemical basis of FANCD2 monoubiquitination.Rajendra E et al
279865922017The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2.Swuec P et al
279863712017Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway.van Twest S et al

Other Information

Locus ID:

NCBI: 2187
MIM: 300515
HGNC: 3583
Ensembl: ENSG00000181544


dbSNP: 2187
ClinVar: 2187
TCGA: ENSG00000181544


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Fanconi anemia pathwayKEGGko03460
Fanconi anemia pathwayKEGGhsa03460
FA core complexKEGGhsa_M00413
FA core complexKEGGM00413
Fanconi Anemia PathwayREACTOMER-HSA-6783310

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
155028272004X-linked inheritance of Fanconi anemia complementation group B.89
183020192009Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families.34
183020192009Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families.34
156116322005New advances in the DNA damage response network of Fanconi anemia and BRCA proteins. FAAP95 replaces BRCA2 as the true FANCB protein.23
219102172011X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations.17
166794912006Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome.13
195366492009The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features.13
203326572010Inactivation of the tumor suppressor genes causing the hereditary syndromes predisposing to head and neck cancer via promoter hypermethylation in sporadic head and neck cancers.12
179031712007Human Mus81 and FANCB independently contribute to repair of DNA damage during replication.9
291939042018Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype.8


Sylvie van Twest ; Andrew Deans

FANCB (FA complementation group B)

Atlas Genet Cytogenet Oncol Haematol. 2019-02-01

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