FANCL (FA complementation group L)

Alias (NCBI)	FA Complementation Group L
	Fanconi Anemia-Associated Polypeptide Of 43 KDa
	RING-Type E3 Ubiquitin Transferase FANCL
	Fanconi Anemia Complementation Group L
	E3 Ubiquitin-Protein Ligase FANCL
	Fanconi Anemia Group L Protein
	PHD finger protein 9
	PHF9
	FAAP43
	POG
HGNC (Hugo)	FANCL
HGNC Alias symb	FLJ10335
	FAAP43
	Pog
HGNC Previous name	PHF9
HGNC Previous name	PHD finger protein 9
	Fanconi anemia complementation group L
LocusID (NCBI)	55120
Atlas_Id	40529
Location	FANCL is located on 2p16.1 which is the short arm (p) of chromosome 2 at position 16.1 between base pairs 58,159,243 to 58,241,681.  [Link to chromosome band 2p16]
Location_base_pair	Starts at 58159247 and ends at 58241325 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping FANCL.png]
	Figure 1: Genomic context of FANCL on chromosome 2 (Adapted from NCBI).

	Figure 2: Exons in FANCL gene. Colour coded to indicate ELF, DRWD, and RING finger domains. Adapted from Chandrasekharappa et al. 2013.
Description	The FANCL gene encodes FANCL protein comprised of 375 amino acids with a molecular mass of 42905 Da. FANCL is comprised of 3 domains, an N-terminal E2-like fold (ELF), a novel double-RWD (DRWD) and C-terminal RING domain (Hodson, Purkiss et al., 2014).
Expression	From total RNA sequencing, FANCL was found to be expressed in adrenal gland (RPKM 2.1), prostate (RPKM 2.34), thymus (RPKM 2.1), and thyroid (RPKM 2.2) (Bioproject PRJNA280600 (PMID 25970244 ). In another RNA sequencing project on 27 different tissues from 95 human individuals, FANCL was highly expressed in adrenal gland (RPKM 16.8), endometrium (RPKM 10.6), lymph nodes (RPKM 8.5), ovary (RPKM 9.2), prostate (RPKM 8.5), and testis (RPKM 12) (Bioproject PRJEB4337, PMID 24309898).
	Figure 3: A) Schematic of D2 monoubiquitination by E3 RING ligase FANCL and E2 conjugating enzyme. B) Ribbon diagram of FANCL with ELF domain (brown), DRWD domain (green), and RING domain (green). C) Surface representation of protein binding domains on FANCL. The binding patch for ubiquitin (orange) is within the ELF domain, while the substrate binding domain (red) is in the DRWD domain, and the Ube2t binding domain (light purple) is in the RING domain. Figure from Specificity and disease in the ubiquitin system by Viduth K. Chaugule and Helen Walden in Biochemical Society Transactions Feb 2016, 44 (1) 212-227; DOI: 10.1042/BST20150209.
Function	FANCL the catalytically active part of the 9 protein Fanconi anemia (FA) core complex comprised of FANCB, FAAP100, FANCA, FANCG, FAAP20, FANCC, FANCE and FANCF that forms in response to DNA damage incurred during DNA replication in S-phase, or to detection of interstand cross links (ICL) (Ceccaldi, Sarangi et al., 2016). FANCL is an E3 ubiquitin ligase that specifically monoubiquitinates FANCD2 (at lysine 561) and FANCI (at lysine 523) (ID2; Note the FANCD2-FANCI heterodimer "ID2" must not to be confused with the gene ID2) in the presence ofUBE2T (FANCT) to signal downstream DNA repair proteins. FANCL is comprised of 3 distinct functional domains: the RING domain interacts with the E2 conjugating enzyme UBE2T (FANCT), the central DRWD domain interacts with FANCD2, and the N-terminal E2-like fold domain (ELF) domain interacts with ubiquitin (Hodson et al., 2014, Miles, Frost et al., 2015). Within the core complex, FANCL interacts as a subcomplex with FANCB and FAAP100 (Huang, Leung et al., 2014, van Twest, Murphy et al., 2017); both proteins stabilize FANCL (Rajendra, Oestergaard et al., 2014), and enhance it's activity 5-fold in vitro assays (Ling, Ishiai et al., 2007). Along with FANCA, FANCG, FANCF, FANCL was found to interact directly with hairy enhancer of split 1 ( HES1), which is a part of the NOTCH1 developmental pathway involved hematopoietic stem cell (HSC) self-renewal (Tremblay, Huang et al., 2008). Depletion of HES1 from cells resulted in FA-like phenotype with disrupted interaction between individual core complex proteins, increased cell sensitivity to DNA crosslinking agents, and reduced MMC-induced ID2 monoubiquitination (Tremblay et al., 2008). Finally HES1 did not interact FA-mutated core complex proteins. HSC defects and eventual bone marrow failure in FA patients may be linked to inability of HES1 to interact with a defective core complex (Tremblay et al., 2008, Tremblay, Huang et al., 2018).
	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, FANCD1, 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

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