fanconi anemia complementation group l protein


Summary: An E3 UBIQUITIN LIGASE that plays a key role in the DNA damage response pathway of FANCONI ANEMIA PROTEINS. It is associated with mono-ubiquitination of FANCD2 PROTEIN and the redistribution of FANCD2 to nuclear foci containing BRCA1 PROTEIN.

Top Publications

  1. Polito D, Cukras S, Wang X, Spence P, Moreau L, D Andrea A, et al. The carboxyl terminus of FANCE recruits FANCD2 to the Fanconi Anemia (FA) E3 ligase complex to promote the FA DNA repair pathway. J Biol Chem. 2014;289:7003-10 pubmed publisher
    ..Intriguingly, ectopic expression of the FANCE C terminus fragment alone in FA normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair. ..
  2. Seki S, Ohzeki M, Uchida A, Hirano S, Matsushita N, Kitao H, et al. A requirement of FancL and FancD2 monoubiquitination in DNA repair. Genes Cells. 2007;12:299-310 pubmed
    ..These data establish the role of FANCL and FancD2 monoubiquitination in HR repair. ..
  3. Ling C, Ishiai M, Ali A, Medhurst A, Neveling K, Kalb R, et al. FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. EMBO J. 2007;26:2104-14 pubmed
    ..Our study identifies FAAP100 as a new critical component of the FA-BRCA DNA damage response network. ..
  4. Alpi A, Pace P, Babu M, Patel K. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008;32:767-77 pubmed publisher
    ..This work therefore establishes a system that provides mechanistic insight into the functions of FANCL and FANCI in the catalysis of FANCD2 monoubiquitination. ..
  5. Panneerselvam J, Park H, Zhang J, Dudimah F, Zhang P, Wang H, et al. FAVL impairment of the Fanconi anemia pathway promotes the development of human bladder cancer. Cell Cycle. 2012;11:2947-55 pubmed publisher
    ..These results enhance our understanding the pathogenesis of human bladder cancer, holding a promise to develop additional effective tools to fight human bladder cancer. ..
  6. Dao K, Rotelli M, Petersen C, Kaech S, Nelson W, Yates J, et al. FANCL ubiquitinates ?-catenin and enhances its nuclear function. Blood. 2012;120:323-34 pubmed publisher
    ..Together, these results suggest that diminished Wnt/?-catenin signaling may be an underlying molecular defect in FANCL-deficient hematopoietic stem cells leading to their accelerated loss. ..
  7. Rosado I, Langevin F, Crossan G, Takata M, Patel K. Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway. Nat Struct Mol Biol. 2011;18:1432-4 pubmed publisher
    ..These results define a fundamental role for the combined action of formaldehyde catabolism and DNA cross-link repair in vertebrate cell survival...
  8. Hodson C, Cole A, Lewis L, Miles J, Purkiss A, Walden H. Structural analysis of human FANCL, the E3 ligase in the Fanconi anemia pathway. J Biol Chem. 2011;286:32628-37 pubmed publisher
    ..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. ..
  9. Medhurst A, Laghmani E, Steltenpool J, Ferrer M, Fontaine C, de Groot J, et al. Evidence for subcomplexes in the Fanconi anemia pathway. Blood. 2006;108:2072-80 pubmed

More Information


  1. Marek L, Bale A. Drosophila homologs of FANCD2 and FANCL function in DNA repair. DNA Repair (Amst). 2006;5:1317-26 pubmed
    ..Because of the lack of other FA genes, further studies will determine whether the conserved FA genes function as the minimal machinery or whether additional genes are involved in the Drosophila FA pathway. ..
  2. Geng L, Huntoon C, Karnitz L. RAD18-mediated ubiquitination of PCNA activates the Fanconi anemia DNA repair network. J Cell Biol. 2010;191:249-57 pubmed publisher
    ..Collectively, these experiments identify RAD18-mediated PCNA monoubiquitination as a central hub for the mobilization of the FA pathway by promoting FANCL-mediated FANCD2 monoubiquitylation. ..
  3. Zhang J, Zhao D, Park H, Wang H, Dyer R, Liu W, et al. FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth. J Clin Invest. 2010;120:1524-34 pubmed publisher
    ..We further believe that these data will prove useful for developing additional tools for fighting human cancer. ..
  4. Meetei A, Yan Z, Wang W. FANCL replaces BRCA1 as the likely ubiquitin ligase responsible for FANCD2 monoubiquitination. Cell Cycle. 2004;3:179-81 pubmed
    ..Our data support the notion that FANCL, but not BRCA1, is the likely ligase for FANCD2 monoubiquitination. ..
  5. Zhang Y, Zhou X, Zhao L, Li C, Zhu H, Xu L, et al. UBE2W interacts with FANCL and regulates the monoubiquitination of Fanconi anemia protein FANCD2. Mol Cells. 2011;31:113-22 pubmed publisher
    ..These results indicate that UBE2W regulates FANCD2 monoubiquitination by mechanisms different from UBE2T and HRR6. It may provide an additional regulatory step in the activation of the FA pathway. ..
  6. Cole A, Lewis L, Walden H. The structure of the catalytic subunit FANCL of the Fanconi anemia core complex. Nat Struct Mol Biol. 2010;17:294-8 pubmed publisher
    ..Binding assays show that the DRWD domain, but not the ELF domain, is responsible for substrate binding. ..
  7. Meetei A, de Winter J, Medhurst A, Wallisch M, Waisfisz Q, van de Vrugt H, et al. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat Genet. 2003;35:165-70 pubmed
    ..Our data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2. ..
  8. Meetei A, Medhurst A, Ling C, Xue Y, Singh T, Bier P, et al. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005;37:958-63 pubmed
    ..Our data suggest an evolutionary link between Fanconi anemia-associated proteins and DNA repair; FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA. ..
  9. Gurtan A, Stuckert P, D Andrea A. The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly. J Biol Chem. 2006;281:10896-905 pubmed
    ..We propose a model in which FANCL, via its WD40 region, binds the FA complex and, via its PHD, recruits an as-yet-unidentified E2 for mono-ubiquitination of FANCD2. ..
  10. Machida Y, Machida Y, Chen Y, Gurtan A, Kupfer G, D Andrea A, et al. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol Cell. 2006;23:589-96 pubmed
    ..Therefore, UBE2T is the E2 in the Fanconi anemia pathway and has a self-inactivation mechanism that could be important for negative regulation of the Fanconi anemia pathway. ..
  11. Alpi A, Langevin F, Mosedale G, Machida Y, Dutta A, Patel K. UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination. Mol Cell Biol. 2007;27:8421-30 pubmed
    ..FANCD2 monoubiquitination is therefore not regulated by multiprotein complex assembly but by the formation of an active E2/E3 holoenzyme on chromatin. ..
  12. Longerich S, San Filippo J, Liu D, Sung P. FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL. J Biol Chem. 2009;284:23182-6 pubmed publisher
    ..We also demonstrate that FANCI can be ubiquitinated on Lys-523 by the UBE2T-FANCL pair in vitro. These findings should facilitate future efforts directed at elucidating molecular aspects of the FA pathway. ..
  13. Zhang J, Wang X, Lin C, Couch F, Fei P. Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells. Cancer Biol Ther. 2006;5:1632-6 pubmed
    ..This suggests that the correlation of an intact FA-BRCA pathway with MMC resistance may emerge as a common mechanism underlying resistance to DNA crosslinking agents in cancer patients. ..
  14. Meier D, Schindler D. Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements. PLoS ONE. 2011;6:e22911 pubmed publisher
    ..These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters. ..
  15. Hess C, Ameziane N, Schuurhuis G, Errami A, Denkers F, Kaspers G, et al. Hypermethylation of the FANCC and FANCL promoter regions in sporadic acute leukaemia. Cell Oncol. 2008;30:299-306 pubmed
    ..In addition, this is the first report to describe hypermethylation of FANCC and FANCL. This warrants the investigation of multiple FA-BRCA genes in other malignancies. ..
  16. Longerich S, Kwon Y, Tsai M, Hlaing A, Kupfer G, Sung P. Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA. Nucleic Acids Res. 2014;42:5657-70 pubmed publisher
    ..These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ..
  17. Akbari M, Malekzadeh R, Lepage P, Roquis D, Sadjadi A, Aghcheli K, et al. Mutations in Fanconi anemia genes and the risk of esophageal cancer. Hum Genet. 2011;129:573-82 pubmed publisher
    ..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. ..
  18. Dao K, Rotelli M, Brown B, Yates J, Rantala J, Tognon C, et al. The PI3K/Akt1 pathway enhances steady-state levels of FANCL. Mol Biol Cell. 2013;24:2582-92 pubmed publisher
  19. Zhang Y, Zhou X, Huang P. Fanconi anemia and ubiquitination. J Genet Genomics. 2007;34:573-80 pubmed
    ..In a word, the FANCD2 activity adjusted exquisitely by ubiquitination and/or deubiquitination in vivo may co-regulate the FA pathway involving in variant DNA repair pathway. ..
  20. Garcia M, Fernandez V, Osorio A, Barroso A, Fernandez F, Urioste M, 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;30:1898-902 pubmed publisher
    ..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. ..
  21. Wu W, Liu Y, Zhou Q, Wang Q, Luo F, Xu Z, et al. Novel homozygous FANCL mutation and somatic heterozygous SETBP1 mutation in a Chinese girl with Fanconi Anemia. Eur J Med Genet. 2017;60:369-373 pubmed publisher
    ..The somatic gene mutation and copy number aberrations could be used to monitor disease progression and the clinical findings provide further information for genotype-phenotype correlation for FA-L. ..
  22. Kitao H, Nanda I, Sugino R, Kinomura A, Yamazoe M, Arakawa H, et al. FancJ/Brip1 helicase protects against genomic losses and gains in vertebrate cells. Genes Cells. 2011;16:714-27 pubmed publisher
    ..These results collectively suggest that, unlike in C. elegans, actions of vertebrate FANCJ to promote genome stability may not be limited to protection against the G4-mediated gene deletions. ..
  23. Chandrasekharappa S, Lach F, Kimble D, Kamat A, Teer J, Donovan F, et al. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood. 2013;121:e138-48 pubmed publisher
    ..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. ..
  24. Rajendra E, Oestergaard V, Langevin F, Wang M, Dornan G, Patel K, et al. The genetic and biochemical basis of FANCD2 monoubiquitination. Mol Cell. 2014;54:858-69 pubmed publisher
    ..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...
  25. Panneerselvam J, Xie G, Che R, Su M, Zhang J, Jia W, et al. Distinct Metabolic Signature of Human Bladder Cancer Cells Carrying an Impaired Fanconi Anemia Tumor-Suppressor Signaling Pathway. J Proteome Res. 2016;15:1333-41 pubmed publisher
    ..Furthermore, this study provides novel insights into how to translate FA basic research into strategies for producing effective biomarkers in human cancer diagnosis and prognosis. ..
  26. Chandrasekharappa S, Chinn S, Donovan F, Chowdhury N, Kamat A, Adeyemo A, et al. Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50. Cancer. 2017;123:3943-3954 pubmed publisher
    ..In the current cohort, the increased mutation load of FANCD2, FANCE, and FANCL variants among younger patients with HNSCC indicates the importance of the FA pathway in HNSCC. Cancer 2017;123:3943-54. © 2017 American Cancer Society. ..
  27. Zhao Q, Zhou Y, Cao Z, Zhu H, Huang P, Lu B. Germ-cell specific protein gametogenetin protein 2 (GGN2), expression in the testis, and association with intracellular membrane. Mol Reprod Dev. 2005;72:31-9 pubmed
    ..Like GGN1, GGN2 was also possibly involved in cell trafficking. The possible involvement of GGN2 in acrosome biogenesis was proposed. ..
  28. Godthelp B, Wiegant W, Waisfisz Q, Medhurst A, Arwert F, Joenje H, et al. Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/BRCA2. Mutat Res. 2006;594:39-48 pubmed
  29. Rodriguez Mari A, Canestro C, Bremiller R, Nguyen Johnson A, Asakawa K, Kawakami K, et al. Sex reversal in zebrafish fancl mutants is caused by Tp53-mediated germ cell apoptosis. PLoS Genet. 2010;6:e1001034 pubmed publisher
  30. Yuan C, Xu N, Liao J. Switch of FANCL, a key FA-BRCA component, between tumor suppressor and promoter by alternative splicing. Cell Cycle. 2012;11:3356 pubmed publisher
    ..Comment on: Panneerselvam J, et al. Cell Cycle 2012; 11:2947-55. ..
  31. Zhao Q, Lu B, Huang P. [Functions of FANCL in primordial germ cell formation and Fanconi anemia]. Yi Chuan Xue Bao. 2005;32:993-1000 pubmed
    ..FANCL is involved in proliferation of PGCs in early embryo stage, and development of germ cells in adult. ..
  32. Juko Pecirep I, Ivansson E, Gyllensten U. Evaluation of Fanconi anaemia genes FANCA, FANCC and FANCL in cervical cancer susceptibility. Gynecol Oncol. 2011;122:377-81 pubmed publisher
    ..02). The associations did not withstand correction for multiple testing. The current study does not support that genetic variation in FANCA, FANCC or FANCL genes affects susceptibility to cervical cancer in the Swedish population. ..
  33. Ali A, Kirby M, Jansen M, Lach F, Schulte J, Singh T, 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:E761-70 pubmed publisher
    ..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. ..
  34. Fan Q, Zhang F, Barrett B, Ren K, Andreassen P. A role for monoubiquitinated FANCD2 at telomeres in ALT cells. Nucleic Acids Res. 2009;37:1740-54 pubmed publisher
    ..Thus, the FA pathway has a novel function in ALT telomere maintenance related to DNA repair. ALT telomere maintenance is therefore one mechanism by which monoubiquitinated FANCD2 may promote genetic stability. ..
  35. Wang L, Stone S, Hoatlin M, Gautier J. Fanconi anemia proteins stabilize replication forks. DNA Repair (Amst). 2008;7:1973-81 pubmed publisher
    ..Together, our data suggest that FA proteins play a role in replication restart at collapsed replication forks. ..