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FANCL; Fanconi anemia, complementation group L (2p16.1)

Gene Summary

Gene:FANCL; Fanconi anemia, complementation group L
Aliases: POG, PHF9, FAAP43
Location:2p16.1
Summary:The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group L. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase FANCL
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (13)

Pathways:

What pathways are this gene/protein implicaed in?
- Tryptophan metabolism KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (1)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Fanconi AnaemiaFanconi Anemia - Complementation Group L
See: More details below...
View Publications29

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Fanconi Anemia - Complementation Group L

Latest Publications

Rajendra E, Oestergaard VH, Langevin F, et al.
The genetic and biochemical basis of FANCD2 monoubiquitination.
Mol Cell. 2014; 54(5):858-69 [PubMed] Free Access to Full Article Related Publications
Fanconi anaemia (FA) is a cancer predisposition syndrome characterized by cellular sensitivity to DNA interstrand crosslinkers. The molecular defect in FA is an impaired DNA repair pathway. The critical event in activating this pathway is monoubiquitination of FANCD2. In vivo, a multisubunit FA core complex catalyzes this step, but its mechanism is unclear. Here, we report purification of a native avian FA core complex and biochemical reconstitution of FANCD2 monoubiquitination. This demonstrates that the catalytic FANCL E3 ligase subunit must be embedded within the complex for maximal activity and site specificity. We genetically and biochemically define a minimal subcomplex comprising just three proteins (FANCB, FANCL, and FAAP100) that functions as the monoubiquitination module. Residual FANCD2 monoubiquitination activity is retained in cells defective for other FA core complex subunits. This work describes the in vitro reconstitution and characterization of this multisubunit monoubiquitin E3 ligase, providing key insight into the conserved FA DNA repair pathway.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCD2


Chandrasekharappa SC, Lach FP, Kimble DC, et al.
Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia.
Blood. 2013; 121(22):e138-48 [PubMed] Free Access to Full Article Related Publications
Current methods for detecting mutations in Fanconi anemia (FA)-suspected patients are inefficient and often miss mutations. We have applied recent advances in DNA sequencing and genomic capture to the diagnosis of FA. Specifically, we used custom molecular inversion probes or TruSeq-enrichment oligos to capture and sequence FA and related genes, including introns, from 27 samples from the International Fanconi Anemia Registry at The Rockefeller University. DNA sequencing was complemented with custom array comparative genomic hybridization (aCGH) and RNA sequencing (RNA-seq) analysis. aCGH identified deletions/duplications in 4 different FA genes. RNA-seq analysis revealed lack of allele specific expression associated with a deletion and splicing defects caused by missense, synonymous, and deep-in-intron variants. The combination of TruSeq-targeted capture, aCGH, and RNA-seq enabled us to identify the complementation group and biallelic germline mutations in all 27 families: FANCA (7), FANCB (3), FANCC (3), FANCD1 (1), FANCD2 (3), FANCF (2), FANCG (2), FANCI (1), FANCJ (2), and FANCL (3). FANCC mutations are often the cause of FA in patients of Ashkenazi Jewish (AJ) ancestry, and we identified 2 novel FANCC mutations in 2 patients of AJ ancestry. We describe here a strategy for efficient molecular diagnosis of FA.

Related: CGH Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCA FANCC FANCD2 FANCG FANCB gene


Panneerselvam J, Park HK, Zhang J, et al.
FAVL impairment of the Fanconi anemia pathway promotes the development of human bladder cancer.
Cell Cycle. 2012; 11(15):2947-55 [PubMed] Free Access to Full Article Related Publications
Effectiveness of DNA cross-linking drugs in the treatment of bladder cancer suggests that bladder cancer cells may have harbored an insufficient cellular response to DNA cross-link damage, which will sensitize cells to DNA cross-linking agents. Cell sensitivity benefits from deficient DNA damage responses, which, on the other hand, can cause cancer. Many changed cellular signaling pathways are known to be involved in bladder tumorigenesis; however, DNA cross-link damage response pathway [Fanconi anemia (FA) pathway], whose alterations appear to be a plausible cause of the development of bladder cancer, remains an under-investigated area in bladder cancer research. In this study, we found FAVL (variant of FA protein L--FANCL) was elevated substantially in bladder cancer tissues examined. Ectopic expression of FAVL in bladder cancer cells as well as normal human cells confer an impaired FA pathway and hypersensitivity to Mitomycin C, similar to those found in FA cells, indicating that FAVL elevation may possess the same tumor promotion potential as an impaired FA pathway harbored in FA cells. Indeed, a higher level of FAVL expression can promote the growth of bladder cancer cells in vitro and in vivo, which, at least partly, results from FAVL perturbation of FANCL expression, an essential factor for the activation of the FA pathway. Moreover, a higher level of FAVL expression was found to be associated with chromosomal instability and the invasiveness of bladder cancer cells. Collectively, FAVL elevation can increase the tumorigenic potential of bladder cancer cells, including the invasive potential that confers the development of advanced bladder cancer. These results enhance our understanding the pathogenesis of human bladder cancer, holding a promise to develop additional effective tools to fight human bladder cancer.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology Mitomycin Signal Transduction Bladder Cancer Bladder Cancer - Molecular Biology


Dao KH, Rotelli MD, Petersen CL, et al.
FANCL ubiquitinates β-catenin and enhances its nuclear function.
Blood. 2012; 120(2):323-34 [PubMed] Free Access to Full Article Related Publications
Bone marrow failure is a nearly universal complication of Fanconi anemia. The proteins encoded by FANC genes are involved in DNA damage responses through the formation of a multisubunit nuclear complex that facilitates the E3 ubiquitin ligase activity of FANCL. However, it is not known whether loss of E3 ubiquitin ligase activity accounts for the hematopoietic stem cell defects characteristic of Fanconi anemia. Here we provide evidence that FANCL increases the activity and expression of β-catenin, a key pluripotency factor in hematopoietic stem cells. We show that FANCL ubiquitinates β-catenin with atypical ubiquitin chain extension known to have nonproteolytic functions. Specifically, β-catenin modified with lysine-11 ubiquitin chain extension efficiently activates a lymphocyte enhancer-binding factor-T cell factor reporter. We also show that FANCL-deficient cells display diminished capacity to activate β-catenin leading to reduced transcription of Wnt-responsive targets c-Myc and Cyclin D1. Suppression of FANCL expression in normal human CD34(+) stem and progenitor cells results in fewer β-catenin active cells and inhibits expansion of multilineage progenitors. Together, these results suggest that diminished Wnt/β-catenin signaling may be an underlying molecular defect in FANCL-deficient hematopoietic stem cells leading to their accelerated loss.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCC Signal Transduction CTNNB1 gene


van de Vrugt HJ, Koomen M, Bakker S, et al.
Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg.
DNA Repair (Amst). 2011; 10(12):1252-61 [PubMed] Related Publications
Fanconi anemia (FA) is a heritable disease characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. The 15 identified FA genes operate in a molecular pathway to preserve genomic integrity. Within this pathway the FA core complex operates as an ubiquitin ligase that activates the complex of FANCD2 and FANCI to coordinate DNA repair. The FA core complex is formed by at least 12 proteins. However, only the FANCL subunit displays ubiquitin ligase activity. FANCA and FANCG are members of the FA core complex for which no other functions have been described than to participate in protein interactions. In this study we generated mice with combined null alleles for Fanca and Fancg to identify extended functions for these genes by characterizing the double mutant mice and cells. Double mutant a(-/-)/g(-/-) mice were born at near Mendelian frequencies without apparent developmental abnormalities. Histological analysis of a(-/-)/g(-/-) mice revealed a Leydig cell hyperplasia and frequent vacuolization of Sertoli cells in testes, while ovaries were depleted from developing follicles and displayed an interstitial cell hyperplasia. These gonadal aberrations were associated with a compromised fertility of a(-/-)/g(-/-) males and females. During the first year of life a(-/-)/g(-/-) did not develop malignancies or bone marrow failure. At the cellular level a(-/-)/g(-/-), Fanca(-/-), and Fancg(-/-) cells proved equally compromised in DNA crosslink and homology-directed repair. Overall the phenotype of a(-/-)/g(-/-) double knockout mice and cells appeared highly similar to the phenotype of Fanca or Fancg single knockouts. The lack of an augmented phenotype suggest that null mutations in Fanca or Fancg are fully epistatic, making additional important functions outside of the FA core complex highly unlikely.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCA FANCG


Rodríguez-Marí A, Postlethwait JH
The role of Fanconi anemia/BRCA genes in zebrafish sex determination.
Methods Cell Biol. 2011; 105:461-90 [PubMed] Related Publications
Fanconi anemia (FA) is a human disease of bone marrow failure, leukemia, squamous cell carcinoma, and developmental anomalies, including hypogonadism and infertility. Bone marrow transplants improve hematopoietic phenotypes but do not prevent other cancers. FA arises from mutation in any of the 15 FANC genes that cooperate to repair double stranded DNA breaks by homologous recombination. Zebrafish has a single ortholog of each human FANC gene and unexpectedly, mutations in at least two of them (fancl and fancd1(brca2)) lead to female-to-male sex reversal. Investigations show that, as in human, zebrafish fanc genes are required for genome stability and for suppressing apoptosis in tissue culture cells, in embryos treated with DNA damaging agents, and in meiotic germ cells. The sex reversal phenotype requires the action of Tp53 (p53), an activator of apoptosis. These results suggest that in normal sex determination, zebrafish oocytes passing through meiosis signal the gonadal soma to maintain expression of aromatase, an enzyme that converts androgen to estrogen, thereby feminizing the gonad and the individual. According to this model, normal male and female zebrafish differ in genetic factors that control the strength of the late meiotic oocyte-derived signal, probably by regulating the number of meiotic oocytes, which environmental factors can also alter. Transcripts from fancd1(brca2) localize at the animal pole of the zebrafish oocyte cytoplasm and are required for normal oocyte nuclear architecture, for normal embryonic development, and for preventing ovarian tumors. Embryonic DNA repair and sex reversal phenotypes provide assays for the screening of small molecule libraries for therapeutic substances for FA.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology


Meier D, Schindler D
Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.
PLoS One. 2011; 6(8):e22911 [PubMed] Free Access to Full Article Related Publications
The Fanconi anemia (FA) gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M) that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS). In the 5' region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3' regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs), and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCA FANCC FANCE FANCF FANCG FANCB gene FANCM gene


Hodson C, Cole AR, Lewis LP, et al.
Structural analysis of human FANCL, the E3 ligase in the Fanconi anemia pathway.
J Biol Chem. 2011; 286(37):32628-37 [PubMed] Free Access to Full Article Related Publications
The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links. At the heart of this pathway is the monoubiquitination of the FANCI-FANCD2 (ID) complex by the multiprotein "core complex" containing the E3 ubiquitin ligase FANCL. Vertebrate organisms have the eight-protein core complex, whereas invertebrates apparently do not. We report here the structure of the central domain of human FANCL in comparison with the recently solved Drosophila melanogaster FANCL. Our data represent the first structural detail into the catalytic core of the human system and reveal that the central fold of FANCL is conserved between species. However, there are macromolecular differences between the FANCL proteins that may account for the apparent distinctions in core complex requirements between the vertebrate and invertebrate FA pathways. In addition, we characterize the binding of human FANCL with its partners, Ube2t, FANCD2, and FANCI. Mutational analysis reveals which residues are required for substrate binding, and we also show the domain required for E2 binding.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCD2


Garner E, Smogorzewska A
Ubiquitylation and the Fanconi anemia pathway.
FEBS Lett. 2011; 585(18):2853-60 [PubMed] Free Access to Full Article Related Publications
The Fanconi anemia (FA) pathway maintains genome stability through co-ordination of DNA repair of interstrand crosslinks (ICLs). Disruption of the FA pathway yields hypersensitivity to interstrand crosslinking agents, bone marrow failure and cancer predisposition. Early steps in DNA damage dependent activation of the pathway are governed by monoubiquitylation of FANCD2 and FANCI by the intrinsic FA E3 ubiquitin ligase, FANCL. Downstream FA pathway components and associated factors such as FAN1 and SLX4 exhibit ubiquitin-binding motifs that are important for their DNA repair function, underscoring the importance of ubiquitylation in FA pathway mediated repair. Importantly, ubiquitylation provides the foundations for cross-talk between repair pathways, which in concert with the FA pathway, resolve interstrand crosslink damage and maintain genomic stability.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology Signal Transduction


Akbari MR, Malekzadeh R, Lepage P, et al.
Mutations in Fanconi anemia genes and the risk of esophageal cancer.
Hum Genet. 2011; 129(5):573-82 [PubMed] Related Publications
The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. Previously, we reported a strong familial component of ESCC among Turkmens, who constitute approximately one-half of the population of this region. We hypothesized that the genes which cause Fanconi anemia might be candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del), one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three patients had a strong family history of ESCC. In addition, four patients (out of 746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none of 1,373 matched controls (OR = 16.7, 95% CI = 6.2-44.2, P = 0.01). The p. Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95% CI = 1.97-6.91, P = 0.0002). In summary, both heterozygous and homozygous mutations in several Fanconi anemia-predisposing genes are associated with an increased risk of ESCC in Iran.

Related: Cancer of the Esophagus Esophageal Cancer Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCD2 FANCE BRCA2


García MJ, Fernández V, Osorio A, et al.
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. 2009; 30(11):1898-902 [PubMed] Related Publications
Fanconi Anemia (FA) is a rare recessive syndrome characterized by cellular hypersensitivity to DNA-cross-linking agents. To date, 13 FA complementation groups have been described and all 13 genes associated to each of these groups have been currently identified. Three of the known FA genes are also high-risk (FANCD1/BRCA2) or moderate-risk (FANCN/PALB2 and FANCJ/BRIP1) breast cancer susceptibility genes, which makes all members of the FA pathway particularly attractive breast cancer candidate genes. Most FA genes have been screened for mutations in breast cancer families negative for BRCA1/2 mutations but the role of FANCL, FANCM and the recently identified FANCI has not been evaluated to date. This fact and novel data sustaining greater functional relevance of the three genes within the FA pathway prompted us to scrutinize all coding sequences and splicing sites of FANCI, FANCL and FANCM in 95 BRCA1/2-negative index cases from Spanish high-risk breast cancer families. We identified 68 sequence variants of which 24 were coding and 44 non-coding. Six exonic and 26 non-coding variants had not been described previously. None of the coding changes caused clearly pathogenic changes and computational analysis of all non-described intronic variants did not revealed major impact in splicing. With the present study, all known FA genes have been evaluated within the context of breast cancer high-risk predisposition. Our results rule out a major role of FANCI, FANCL and FANCM in familial breast cancer susceptibility, suggesting that among the 13 known FA genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.

Related: Breast Cancer Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCM gene


Thompson LH, Hinz JM
Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights.
Mutat Res. 2009; 668(1-2):54-72 [PubMed] Free Access to Full Article Related Publications
The Fanconi anemia (FA) molecular network consists of 15 "FANC" proteins, of which 13 are associated with mutations in patients with this cancer-prone chromosome instability disorder. Whereas historically the common phenotype associated with FA mutations is marked sensitivity to DNA interstrand crosslinking agents, the literature supports a more global role for FANC proteins in coping with diverse stresses encountered by replicative polymerases. We have attempted to reconcile and integrate numerous observations into a model in which FANC proteins coordinate the following physiological events during DNA crosslink repair: (a) activating a FANCM-ATR-dependent S-phase checkpoint, (b) mediating enzymatic replication-fork breakage and crosslink unhooking, (c) filling the resulting gap by translesion synthesis (TLS) by error-prone polymerase(s), and (d) restoring the resulting one-ended double-strand break by homologous recombination repair (HRR). The FANC core subcomplex (FANCA, B, C, E, F, G, L, FAAP100) promotes TLS for both crosslink and non-crosslink damage such as spontaneous oxidative base damage, UV-C photoproducts, and alkylated bases. TLS likely helps prevent stalled replication forks from breaking, thereby maintaining chromosome continuity. Diverse DNA damages and replication inhibitors result in monoubiquitination of the FANCD2-FANCI complex by the FANCL ubiquitin ligase activity of the core subcomplex upon its recruitment to chromatin by the FANCM-FAAP24 heterodimeric translocase. We speculate that this translocase activity acts as the primary damage sensor and helps remodel blocked replication forks to facilitate checkpoint activation and repair. Monoubiquitination of FANCD2-FANCI is needed for promoting HRR, in which the FANCD1/BRCA2 and FANCN/PALB2 proteins act at an early step. We conclude that the core subcomplex is required for both TLS and HRR occurring separately for non-crosslink damages and for both events during crosslink repair. The FANCJ/BRIP1/BACH1 helicase functions in association with BRCA1 and may remove structural barriers to replication, such as guanine quadruplex structures, and/or assist in crosslink unhooking.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology


Ali AM, Kirby M, Jansen M, et al.
Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group.
Hum Mutat. 2009; 30(7):E761-70 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder characterized by aplastic anemia, cancer susceptibility and cellular sensitivity to DNA crosslinking agents. Eight FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM) and three non-FA proteins (FAAP100, FAAP24 and HES1) form an FA nuclear core complex, which is required for monoubiquitination of the FANCD2-FANCI dimer upon DNA damage. FANCL possesses a PHD/RING-finger domain and is a putative E3 ubiquitin ligase subunit of the core complex. In this study, we report an FA patient with an unusual presentation belonging to the FA-L complementation group. The patient lacks an obvious FA phenotype except for the presence of a café-au-lait spot, mild hypocellularity and a family history of leukemia. The molecular diagnosis and identification of the FA subgroup was achieved by FA complementation assay. We identified bi-allelic novel mutations in the FANCL gene and functionally characterized them. To the best of our knowledge, this is the second reported case belonging to the FA-L complementation group.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology Leukemia


Song L
A possible approach for stem cell gene therapy of Fanconi anemia.
Curr Gene Ther. 2009; 9(1):26-32 [PubMed] Related Publications
Fanconi anemia (FA) is an inherited chromosomal recessive syndrome characterized by cellular hypersensitivity to DNA crosslinking agents and bone marrow failure, which cause aplastic anemia, and an increased incidence of malignancy. 13 complementation groups are currently discovered, and 13 distinct genes have been cloned (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FNACI, FANCJ, FANCL, FANCM, FANCN). Stem cells can theoretically divide to other cells without limit as long as a person is still alive. The stem cells that form blood and immune cells are known as hematopoietic stem cells. Hematopoietic stem cells can be acquired from a Fanconi anemia patient, whereas genomic DNA can be obtained easily from blood cells of a normal person. Normal genes also can be synthesised by PCR method. Normal genomic DNA will be delivered into a patient's stem cells via microinjection or transfection after enzyme digestion; the defective genes might be repaired by homologous genetic recombination. The gene-corrected stem cells can be transplanted into the same patient finally. It is possible that human genomic DNA to be considered as materials for homologous genetic recombination to repair defective genes in vivo. This might be an efficient method for gene therapy, which has no or less immunological rejection for Fanconi anemia and some genetic diseases. Several related observations and experiments are discussed to support this possible means of stem cell gene therapy of Fanconi anemia.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology


Zhang J, Zhao D, Wang H, et al.
FANCD2 monoubiquitination provides a link between the HHR6 and FA-BRCA pathways.
Cell Cycle. 2008; 7(3):407-13 [PubMed] Related Publications
Fanconi Anemia (FA) is a rare genetic disease characterized by chromosome instability mostly resulting from an improper regulation of FANCD2 monoubiquitination. The E2 ubiquitin conjugating enzyme UBE2T along with a multi-protein E3 ubiquitin-ligase complex containing a catalytic subunit FANCL mediates monoubiquitination of FANCD2. However, the upstream events involved in regulating FANCD2 monoubiquitination remain unclear. Here we report that HHR6, human homologs of the yeast ubiquitin-conjugating enzyme Rad6, regulates FANCD2 monoubiquitination in a manner distinct from that of UBE2T. Indeed, although downregulation of HHR6 compromised FANCD2 monoubiquitination and overexpression of HHR6 enhanced FANCD2 monoubiquitination, HHR6 did not directly interact with FANCL. Cells deficient in HHR6, UBE2T or FANCL did, however, all exhibit similar sensitivities to the DNA crosslinking agent mitomycin C (MMC). As an HHR6-induced increase in oncogenic potential could be partially suppressed by co-expression of non-monoubiquitinated FANCD2, a tight regulation of appropriate levels of monoubiquitinated FANCD2 appears to play an important role in tumor suppression. Thus, these results provide further insights into the regulation of FANCD2 monoubiquitination as well as indicate a common link between the FA-BRCA and HHR6 pathways in the maintenance of genome integrity.

Related: Fanconi Anaemia Fanconi Anemia - Molecular Biology FANCD2 Signal Transduction


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Cite this page: Cotterill SJ. FANCL gene, Cancer Genetics Web: http://www.cancerindex.org/geneweb/FANCL.htm Accessed: date

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