FANCB (FA complementation group B)
2019-02-01 Sylvie van Twest , Andrew Deans AffiliationSt Vincents Institute of Medical Research, 9 Princes St, Fitzroy VIC 3065, Australia; [email protected]; [email protected]
Identity
HGNC
LOCATION
Xp22.2
IMAGE
LEGEND
Figure 1: Genomic context of FANCB on chromosome (Adapted from NCBI).
LOCUSID
ALIAS
FAB,FA2,FACB
Abstract
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).
DNA/RNA
Figure 2: Schematic of FANCB gene. Black represents exons (protein coding regions), white represents introns (non-coding). Adapted from McCauley et al. 2011.
Description
FANCB has 10 exons, and the translation start site is in exon 3 (Meetei et al., 2004).
Transcription
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.
Proteins
Description
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).
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.
Expression
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.
Function
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.
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.
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 https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/fancb.
Figure 5: FANCB dimer coordinates FANCD2:FANCI monoubiquitination by two FANCL RING-ligases.
Mutations
Somatic
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
Disease
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).
Prognosis
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).
Diagnostic
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.
Prognosis
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).
Diagnostic
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 18024606 | 2007 | Diagnosis, genetics, and management of inherited bone marrow failure syndromes. | Alter BP et al |
| 23653579 | 2013 | VACTERL-H Association and Fanconi Anemia. | Alter BP et al |
| 27145721 | 2016 | The Fanconi anaemia pathway: new players and new functions. | Ceccaldi R et al |
| 4254647 | 1971 | [Early determination of handicaps in the newborn and infants]. | Frischknecht W et al |
| 16679491 | 2006 | Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome. | Holden ST et al |
| 24910428 | 2014 | Modularized functions of the Fanconi anemia core complex. | Huang Y et al |
| 16896009 | 2006 | DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes. | Kennedy RD et al |
| 17396147 | 2007 | FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. | Ling C et al |
| 21910217 | 2011 | X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations. | McCauley J et al |
| 16720839 | 2006 | Evidence for subcomplexes in the Fanconi anemia pathway. | Medhurst AL et al |
| 1550282 | 1992 | Ketamine 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 |
| 24905007 | 2014 | The genetic and biochemical basis of FANCD2 monoubiquitination. | Rajendra E et al |
| 27986592 | 2017 | The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2. | Swuec P et al |
| 27986371 | 2017 | Mechanism 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
Variants:
dbSNP: 2187
ClinVar: 2187
TCGA: ENSG00000181544
COSMIC: FANCB
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 36172730 | 2022 | [Association of CDH1, FANCB and APC Gene Polymorphisms with Lung Cancer Susceptibility in Chinese Population]. | 0 |
| 36172730 | 2022 | [Association of CDH1, FANCB and APC Gene Polymorphisms with Lung Cancer Susceptibility in Chinese Population]. | 0 |
| 29193904 | 2018 | Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype. | 17 |
| 29491055 | 2018 | Mutational and Functional Analysis of FANCB as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas. | 5 |
| 29193904 | 2018 | Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype. | 17 |
| 29491055 | 2018 | Mutational and Functional Analysis of FANCB as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas. | 5 |
| 21910217 | 2011 | X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations. | 20 |
| 21910217 | 2011 | X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations. | 20 |
| 20332657 | 2010 | Inactivation 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 |
| 20465790 | 2010 | Bony metastases from breast cancer - a study of foetal antigen 2 as a blood tumour marker. | 0 |
| 20332657 | 2010 | Inactivation 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 |
| 20465790 | 2010 | Bony metastases from breast cancer - a study of foetal antigen 2 as a blood tumour marker. | 0 |
| 18302019 | 2009 | Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families. | 39 |
| 18302019 | 2009 | Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families. | 39 |
| 19536649 | 2009 | The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features. | 14 |
Citation
Sylvie van Twest ; Andrew Deans
FANCB (FA complementation group B)
Atlas Genet Cytogenet Oncol Haematol. 2019-02-01
Online version: http://atlasgeneticsoncology.org/gene/49864/fancb-(fa-complementation-group-b)
