FANCB (FA complementation group B)

Alias_names	Fanconi anemia complementation group B
Alias_symbol (synonym)	FAB
	FLJ34064
	FAAP95
Other alias	FA2
	FACB
HGNC (Hugo)	FANCB
LocusID (NCBI)	2187
Atlas_Id	49864
Location	Xp22.2  [Link to chromosome band Xp22]
Location_base_pair	Starts at 14843407 and ends at 14873069 bp from pter ( according to hg19-Feb_2009)  [Mapping FANCB.png]
	Figure 1: Genomic context of FANCB on chromosome (Adapted from NCBI).

	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.

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, & D'Andrea, 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.
	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.

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