Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

FEN1 (flap structure-specific endonuclease 1)

Written2010-01L David Finger, Binghui Shen
Division of Radiation Biology, Department of Cancer Biology, City of Hope National Cancer Center Beckman Research Institute, 1500 E Duarte Road, Duarte, CA 91010-3000, USA

(Note : for Links provided by Atlas : click)


Alias_symbol (synonym)FEN-1
Other aliashFEN-1
HGNC (Hugo) FEN1
LocusID (NCBI) 2237
Atlas_Id 40543
Location 11q12.2  [Link to chromosome band 11q12]
Location_base_pair Starts at 61792637 and ends at 61797242 bp from pter ( according to hg19-Feb_2009)  [Mapping FEN1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
FEN1 (11q12.2) / SULF1 (8q13.2)HS3ST4 (16p12.1) / FEN1 (11q12.2)


  Figure 1.
Description Spans 4561 bp; two exons; one intron (Figure 1).
Transcription Spliced transcript is 2265 bp in length. First exon is 1-351 bp and the second exon comprises 352 to 2265 bps of the spliced mRNA. The open reading frame spans 1142 base pairs (bp 373-1515).


  Figure 2. Structure of human FEN1.
A. Schematic of hFEN1 organization as determined by primary sequence analysis (Shen et al., 1998). The protein is divided into the N-terminal (N), Intermediate (I), C-terminal (C), and extended C-terminal regions colored in blue, green, red, and grey, respectively.
B. Structure of hFEN1 (1UL1) colored according to region. Note: electron density for portions of the I-region and the extended C-terminus were not observed (Sakurai et al., 2005).
C. Topology diagram of hFEN1 (Horton, 2008) colored according to region. Filled triangles and circles indicate structural elements that are conserved in all known FEN1s, whereas open circles and triangles indicate structural elements that vary between phage and archaeal/eukaryotic FEN1s. Yellow stars indicate the relative positions of the active site carboxylate residues that bind the requisite divalent metal ions.
D. Two-dimensional schematic of the hFEN1 structure (Grasby J, U. Sheffield, personal communication). Note: the amino terminus of hFEN1 (true for other archaeal and eukaryotic FEN1s as well) is structured and resides near the active site.
E. Schematic illustration of hFEN1 and its interaction with a double-flap substrate. The duplex DNA 3' of the cleavage site is denoted as the downstream duplex (cyan). The upstream duplex dsDNA (magenta) is 5' to the cleavage site. The 5'-ssDNA flap (brown) likely interacts with the helical arch formed by the I-region (Chapados et al., 2004; Liu et al., 2006; Devos et al., 2007; Nazarkina et al., 2008).
Description Human FEN1 is a metallonuclease comprised of 380 amino acid residues (Nazarkina et al., 2008). The protein has a nuclease core domain composed of the N, I, and C regions and an extended C-terminus (Figure 2A) (Shen et al., 1998). The extended C-terminus is dispensable for nuclease activity, but is important for protein-protein interaction with partners like PCNA and WRN (Brosh et al., 2001; Brosh et al., 2002; Zheng et al., 2005; Zheng et al., 2007; Guo et al., 2008; Nazarkina et al., 2008; Karanja and Livingston, 2009) and contains a bipartite nuclear localization signal (Qiu et al., 2001). Structural studies show that the nuclease core domain of FEN1 has a SAM-like or PIN-like fold with a mixed beta-sheet buttressed on both sides by alpha-helical structure and spanned by an arch-like structure (Figure 2B and C) (Horton, 2008). Moreover, the N and C regions form the saddle-like structure of the protein that binds dsDNA and provide the amino acid residues that bind the requisite divalent ions (Figure 2D). hFEN1 binds two divalent metal ions (Sakurai et al., 2005) and is thought to achieve phosphodiesterase activity using a 'two-metal-ion' mechanism (Yang et al., 2006; Syson et al., 2008). The C-region contains an H3tH motif and binds the downstream dsDNA of the substrate (Figure 3E). The N-region interacts with the upstream dsDNA. Notably, a hydrophobic wedge stacks on the terminal base pair of the upstream duplex closest to the active site and a cleft or pocket binds to a 3'-extrahelical nucleotide. The N and C regions are interrupted by the I-region, which forms an arch that spans the beta-sheet and the active site residues. The arch likely interacts with the 5'-ssDNA flap (Chapados et al., 2004; Liu et al., 2006; Devos et al., 2007; Nazarkina et al., 2008).
Human FEN1 is subject to post-translational modifications, which are thought to regulate hFEN1 activities in vivo (Nazarkina et al., 2008). The extended C-terminal domain can be acetylated in vitro by p300 at four lysine residues (Friedrich-Heineken et al., 2003). A mass spec analysis identified K267 and K375 of hFEN1 as in vivo sites of acetylation (Choudhary et al., 2009). Amino acid residue S187 can be phosphorylated in vitro and in vivo by CDK1-Cyclin A, which regulates the S to G2 transition. S187 phosphorylation has been shown to decrease FEN1 activity in vitro, which is consistent with the role of CDK1-Cyclin A in cell cycle regulation (Henneke et al., 2003).
Expression FEN1 is detectable in all proliferative tissues, but barely detectable in non-proliferative tissues (Warbrick et al., 1998; Kim et al., 2000). FEN1 is often overexpressed in tumor tissues (LaTulippe et al., 2002; Freedland et al., 2003; Iacobuzio-Donahue et al., 2003; Sato et al., 2003; Kim et al., 2005; Krause et al., 2005; Lam et al., 2006; Singh et al., 2008; Nikolova et al., 2009). Furthermore, cancer tissues have been reported to exhibit FEN1 promoter hypomethylation (Singh et al., 2008).
Localisation The localization of FEN1 in human cells is predominantly nuclear (Warbrick et al., 1998; Kim et al., 2000), but is also found in mitochondria (Liu et al., 2008; Szczesny et al., 2008; Kalifa et al., 2009).
  Figure 3. The 3'-flap directs cleavage site specificity. Using double- and single-flap synthetic substrates labeled at the 3'-terminus (indicated by the gray star), the predominant cleavage site is observed to change from the dsDNA-ssDNA junction (single flap - F(5)•T) to one nucleotide into the downstream duplex (double flap - F(5)•T3F). Single-flap substrates have a secondary cleavage site one nucleotide into the duplex that is equivalent to the cleavage site on the double flap substrate. Note: similar studies with 5'-radiolabelling show that a six-nucleotide product is formed with F(5)•T3F, whereas a 5- and 6-nucleotide product are formed with F(5)•T.
Function General biochemistry: Human FEN1 can cleave a wide variety of substrates with a 5' to 3' polarity exo- and endo-nucleolytically, albeit with widely varying levels of efficiency (Shen et al., 2005; Nazarkina et al., 2008). Regardless of substrate and cleavage efficiency, FEN1 phosphodiesterase activity results in 5'-phosphate monoester and 3'-hydroxyl products (Pickering et al., 1999; Yang et al., 2006). Consistent with its in vivo roles, hFEN1 preferentially cleaves substrates bearing a single nucleotide 3'-flap and a 5'-flap of varying length (i.e., double-flaps) (Friedrich-Heineken and Hubscher, 2004). The 3'-flap stabilizes the enzyme-substrate complex and increases subsequent first-order rates of reaction to augment "enzyme commitment" to the forward reaction (Finger et al., 2009). Furthermore, the presence of a 3'-flap on the substrate increases the cleavage site specificity, such that the enzyme cleaves exclusively at the nucleotide that lies one nucleotide into the downstream duplex (Figure 3 and 4A). With a substrate lacking a 3'-flap, the cleavage on the 5'-flap predominantly occurs at the dsDNA-ssDNA flap junction and to a lesser extent one nucleotide into the downstream duplex (Figure 3 and 4B) (Friedrich-Heineken and Hubscher, 2004; Finger et al., 2009).
Okazaki fragment maturation: Cleaves 5'-flap bifurcated nucleic acid flap structures generated by lagging-strand DNA synthesis during Okazaki fragment maturation in the nucleus (Liu et al., 2004; Garg and Burgers, 2005; Shen et al., 2005; Rossi et al., 2006; Nazarkina et al., 2008). Deletion of the FEN1 gene in mammals is embryonically lethal (Larsen et al., 2003), but deletion of its homolog in Saccharomyces cerevisiae, RAD27, is tolerated (Reagan et al., 1995). Studies in haploid yeast have shown that the deletion of RAD27 increases rates of nuclear mitotic recombination, point mutation, reversion, microsatellite instability, and frameshifts (Johnson et al., 1995; Sommers et al., 1995; Tishkoff et al., 1997; Kokoska et al., 1998; Callahan et al., 2003; Navarro et al., 2007). In a similar manner, direct-repeat recombination, chromosome loss, and interhomolog recombination were increased in rad27Δ/rad27Δ diploids (Navarro et al., 2007). In contrast to nuclear DNA, rad27Δ causes a decrease in mitochondrial direct-repeat mediated deletion and mitochondrial microsatellite instability (Kalifa et al., 2009); however, the origins of these decreases are not understood.
Long-patch base excision repair: FEN1 cleaves 5'-flap bifurcated nucleic acid structures generated during nuclear (Nazarkina et al., 2008; Robertson et al., 2009) and mitochondrial long-patch base excision repair (Liu et al., 2008; Kalifa et al., 2009; Robertson et al., 2009). Consistent with the role of FEN1 in mitochondrial long-patch base excision repair in yeast, rad27Δ mutants accumulate point mutations in mitochondrial DNA (Kalifa et al., 2009).
Telomere maintenance: FEN1 has been shown to be important for telomere stability in yeast and mammalian cells by ensuring efficient telomere replication (Parenteau and Wellinger, 1999; Parenteau and Wellinger, 2002; Saharia et al., 2008) and is essential for telomere stability in ALT-positive cells (Saharia and Stewart, 2009). Furthermore, FEN1 forms a complex with telomerase (Sampathi et al., 2009).
  Figure 4. The 3'-flap directs cleavage to ensure that all dsDNA product is ligatable.
A. Schematic illustration of the cleavage products of the double-flap substrate. The 3'-flap is red, the last nucleotide of the 5'-flap is purple, and the downstream duplex terminal base pair is shown in blue and orange. After cleavage, the purple and orange nucleotides are part of the ssDNA product. For the dsDNA product, the red nucleotide forms a base-pair with the blue nucleotide to create a ligatable nick.
B. In a similar manner, cleavage on the single flap substrate, which lacks the red nucleotide, occurs predominantly between the purple and orange nucleotide to create a 5-nucleotide ssDNA product and a ligatable dsDNA product. To a lesser degree, cleavage also occurs at the nucleotide one nucleotide into the downstream duplex to create a 6-nucleotide ssDNA product and a single nucleotide gap dsDNA product. Note: the substrates used in Figure 3 are static structures (i.e., they do not have the ability to equilibrate as in vivo substrates do). See following references for more detail (Kaiser et al., 1999; Kao et al., 2002; Sharma et al., 2004; Nazarkina et al., 2008).
Homology Member of the Rad2 nuclease family (i.e., close cousin to XPG, EXO1, and GEN1) (Lieber, 1997).


Note Two FEN1 polymorphisms have been reported to be associated with an increased risk of lung cancer. The first polymorphism is c.69G>A (rs174538:G>A) and resides in the FEN1 promoter region. The second is c.4150G>T (rs4246215:G>T) and resides in the 3'-UTR of the transcript (Figure 1). Both polymorphisms are associated with decreased FEN1 expression levels (Yang et al., 2009).
DNA sequencing of DNA from tumors and tumor-derived cell lines has revealed mutations in the FEN1 gene that affect nuclease activity (Zheng et al., 2007). Furthermore, studies have shown that mice from two genetic backgrounds that are homozygous for an active site mutation known to alter enzymatic activity in vitro show an increased incidence of cancer (Zheng et al., 2007; Larsen et al., 2008).

Implicated in

Entity Prostate cancer
Oncogenesis A gene expression profile comparing normal, primary tumor, and metastatic prostate tissue samples showed that FEN1 expression is up-regulated in primary and metastatic tumor tissue along with other DNA replication and repair genes (LaTulippe et al., 2002). The level of FEN1 expression has also been positively correlated with tumor Gleason score, and thus, tumor dedifferentiation (Lam et al., 2006). Furthermore, aggressive forms of prostate cancer as defined by the ability to form tumors in SCID mice show a five-fold or greater increase in FEN1 expression in comparison to a nontumorigenic clone (Freedland et al., 2003).
Entity Pancreatic cancer
Oncogenesis Using cDNA microarrays, a global gene expression profile of pancreatic adenocarcinoma identified FEN1 as one of 103 previously unidentified genes that were expressed at higher levels in comparison to normal tissue (Iacobuzio-Donahue et al., 2003).
Entity Gastric cancer
Oncogenesis Using cDNA microarrays and semi-quantitative RT-PCR, FEN1 was shown to be up-regulated in comparison to normal tissue (Kim et al., 2005). Furthermore, using a cancer profiling array and immunohistochemistry, FEN1 was also shown to be up-regulated in stomach cancer (Singh et al., 2008).
Entity Lung cancer
Oncogenesis FEN1 levels were elevated in small cell and non-small-cell cancers in comparison to normal lung controls (Sato et al., 2003). Furthermore, using a cancer profiling array and immunohistochemistry, FEN1 was also shown to be up-regulated at the mRNA and protein level in lung cancer (Singh et al., 2008; Nikolova et al., 2009).
Entity Brain cancer
Oncogenesis Gene expression patterns in neuroblastomas were analyzed using microarrays and confirmed by RT-PCR to show that neuroblastomas with unfavorable clinical outcome express FEN1 at levels 2.7-fold higher than neuroblastomas detected by mass screening (Krause et al., 2005), thereby implying that FEN1 expression level in neuroblastoma could be diagnostic of clinical outcome. Futhermore, FEN1 expression levels are higher in glioblastoma multiforme, primary astrocytoma, anaplastic astrocytoma, and oligoastrocytoma as determined by Western blotting (Nikolova et al., 2009).
Entity Breast cancer
Oncogenesis A cancer profiling array and immunohistochemistry showed increased levels of FEN1 expression at the mRNA and protein levels. In addition, increased expression is likely due to promoter hypomethylation. Furthermore, this study showed that increased FEN1 expression is positively correlated with advanced or higher grace breast tumors (Singh et al., 2008).
Entity Testicular cancer
Oncogenesis Western blotting analysis showed increased levels of FEN1 in 14 out of the 17 seminomas (Nikolova et al., 2009).
Entity Other cancers
Oncogenesis Overexpression of FEN1 at the mRNA level has also been detected in uterine, colon, ovarian, and kidney cancer tissues (Singh et al., 2008). In summary, expression of FEN1 is commonly increased to facilitate cell proliferation in cancer cells due to the pivotal role of FEN1 in DNA replication. However, partial or complete loss of function is also known to facilitate the development of cancer by causing genomic instability in eukaryotes (Navarro et al., 2007; Zheng et al., 2007; Larsen et al., 2008).


Biochemical characterization of the WRN-FEN-1 functional interaction.
Brosh RM Jr, Driscoll HC, Dianov GL, Sommers JA.
Biochemistry. 2002 Oct 8;41(40):12204-16.
PMID 12356323
Mutations in yeast replication proteins that increase CAG/CTG expansions also increase repeat fragility.
Callahan JL, Andrews KJ, Zakian VA, Freudenreich CH.
Mol Cell Biol. 2003 Nov;23(21):7849-60.
PMID 14560028
Structural basis for FEN-1 substrate specificity and PCNA-mediated activation in DNA replication and repair.
Chapados BR, Hosfield DJ, Han S, Qiu J, Yelent B, Shen B, Tainer JA.
Cell. 2004 Jan 9;116(1):39-50.
PMID 14718165
Lysine acetylation targets protein complexes and co-regulates major cellular functions.
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
Science. 2009 Aug 14;325(5942):834-40. Epub 2009 Jul 16.
PMID 19608861
Crystal structure of bacteriophage T4 5' nuclease in complex with a branched DNA reveals how flap endonuclease-1 family nucleases bind their substrates.
Devos JM, Tomanicek SJ, Jones CE, Nossal NG, Mueser TC.
J Biol Chem. 2007 Oct 26;282(43):31713-24. Epub 2007 Aug 9.
PMID 17693399
The 3'-flap pocket of human flap endonuclease 1 is critical for substrate binding and catalysis.
Finger LD, Blanchard MS, Theimer CA, Sengerova B, Singh P, Chavez V, Liu F, Grasby JA, Shen B.
J Biol Chem. 2009 Aug 14;284(33):22184-94. Epub 2009 Jun 11.
PMID 19525235
Heterogeneity of molecular targets on clonal cancer lines derived from a novel hormone-refractory prostate cancer tumor system.
Freedland SJ, Pantuck AJ, Paik SH, Zisman A, Graeber TG, Eisenberg D, McBride WH, Nguyen D, Tso CL, Belldegrun AS.
Prostate. 2003 Jun 1;55(4):299-307.
PMID 12712409
The Fen1 extrahelical 3'-flap pocket is conserved from archaea to human and regulates DNA substrate specificity.
Friedrich-Heineken E, Hubscher U.
Nucleic Acids Res. 2004 May 6;32(8):2520-8. Print 2004.
PMID 15131255
DNA polymerases that propagate the eukaryotic DNA replication fork.
Garg P, Burgers PM.
Crit Rev Biochem Mol Biol. 2005 Mar-Apr;40(2):115-28.
PMID 15814431
Comprehensive mapping of the C-terminus of flap endonuclease-1 reveals distinct interaction sites for five proteins that represent different DNA replication and repair pathways.
Guo Z, Chavez V, Singh P, Finger LD, Hang H, Hegde ML, Shen B.
J Mol Biol. 2008 Mar 28;377(3):679-90. Epub 2007 Nov 4.
PMID 18291413
Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.
Henneke G, Koundrioukoff S, Hubscher U.
Oncogene. 2003 Jul 10;22(28):4301-13.
PMID 12853968
DNA Nucleases.
Horton N.
In Protein-Nucleic Acid Interaction: Structural Biology. C. C. Correll and P. A. Rice. Cambridge, UK, RSCPublishing. 2008;348-349. BOOK SECTION ISBN 978-0-85404-272-2.
Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays.
Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M.
Am J Pathol. 2003 Apr;162(4):1151-62.
PMID 12651607
Requirement of the yeast RTH1 5' to 3' exonuclease for the stability of simple repetitive DNA.
Johnson RE, Kovvali GK, Prakash L, Prakash S.
Science. 1995 Jul 14;269(5221):238-40.
PMID 7618086
A comparison of eubacterial and archaeal structure-specific 5'-exonucleases.
Kaiser MW, Lyamicheva N, Ma W, Miller C, Neri B, Fors L, Lyamichev VI.
J Biol Chem. 1999 Jul 23;274(30):21387-94.
PMID 10409700
Evidence for a role of FEN1 in maintaining mitochondrial DNA integrity.
Kalifa L, Beutner G, Phadnis N, Sheu SS, Sia EA.
DNA Repair (Amst). 2009 Oct 2;8(10):1242-9. Epub 2009 Aug 21.
PMID 19699691
Cleavage specificity of Saccharomyces cerevisiae flap endonuclease 1 suggests a double-flap structure as the cellular substrate.
Kao HI, Henricksen LA, Liu Y, Bambara RA.
J Biol Chem. 2002 Apr 26;277(17):14379-89. Epub 2002 Feb 1.
PMID 11825897
C-terminal flap endonuclease (rad27) mutations: lethal interactions with a DNA ligase I mutation (cdc9-p) and suppression by proliferating cell nuclear antigen (POL30) in Saccharomyces cerevisiae
Karanja KK, Livingston DM.
Genetics. 2009 Sep;183(1):63-78. Epub 2009 Jul 13.
PMID 19596905
Gene expression of flap endonuclease-1 during cell proliferation and differentiation.
Kim IS, Lee MY, Lee IH, Shin SL, Lee SY.
Biochim Biophys Acta. 2000 Apr 17;1496(2-3):333-40.
PMID 10771101
Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells.
Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Kim YS, Kim JG, Kim NS.
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):473-82.
PMID 15701830
Destabilization of yeast micro- and minisatellite DNA sequences by mutations affecting a nuclease involved in Okazaki fragment processing (rad27) and DNA polymerase delta (pol3-t).
Kokoska RJ, Stefanovic L, Tran HT, Resnick MA, Gordenin DA, Petes TD.
Mol Cell Biol. 1998 May;18(5):2779-88.
PMID 9566897
Genome-wide analysis of gene expression in neuroblastomas detected by mass screening.
Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A.
Cancer Lett. 2005 Jul 8;225(1):111-20. Epub 2004 Dec 8.
PMID 15922863
Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease.
LaTulippe E, Satagopan J, Smith A, Scher H, Scardino P, Reuter V, Gerald WL.
Cancer Res. 2002 Aug 1;62(15):4499-506.
PMID 12154061
Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score.
Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS.
BJU Int. 2006 Aug;98(2):445-51.
PMID 16879693
Proliferation failure and gamma radiation sensitivity of Fen1 null mutant mice at the blastocyst stage.
Larsen E, Gran C, Saether BE, Seeberg E, Klungland A.
Mol Cell Biol. 2003 Aug;23(15):5346-53.
PMID 12861020
Early-onset lymphoma and extensive embryonic apoptosis in two domain-specific Fen1 mice mutants.
Larsen E, Kleppa L, Meza TJ, Meza-Zepeda LA, Rada C, Castellanos CG, Lien GF, Nesse GJ, Neuberger MS, Laerdahl JK, William Doughty R, Klungland A.
Cancer Res. 2008 Jun 15;68(12):4571-9.
PMID 18559501
The FEN-1 family of structure-specific nucleases in eukaryotic DNA replication, recombination and repair.
Lieber MR.
Bioessays. 1997 Mar;19(3):233-40.
PMID 9080773
Removal of oxidative DNA damage via FEN1-dependent long-patch base excision repair in human cell mitochondria.
Liu P, Qian L, Sung JS, de Souza-Pinto NC, Zheng L, Bogenhagen DF, Bohr VA, Wilson DM 3rd, Shen B, Demple B.
Mol Cell Biol. 2008 Aug;28(16):4975-87. Epub 2008 Jun 9.
PMID 18541666
The DNA-protein interaction modes of FEN-1 with gap substrates and their implication in preventing duplication mutations.
Liu R, Qiu J, Finger LD, Zheng L, Shen B.
Nucleic Acids Res. 2006 Mar 31;34(6):1772-84. Print 2006.
PMID 16582103
Flap endonuclease 1: a central component of DNA metabolism.
Liu Y, Kao HI, Bambara RA.
Annu Rev Biochem. 2004;73:589-615. (REVIEW)
PMID 15189154
A mutant allele of the transcription factor IIH helicase gene, RAD3, promotes loss of heterozygosity in response to a DNA replication defect in Saccharomyces cerevisiae.
Navarro MS, Bi L, Bailis AM.
Genetics. 2007 Jul;176(3):1391-402. Epub 2007 May 4.
PMID 17483411
[Flap endonuclease-1 and its role in the processes of DNA metabolism in eucaryotic cells]
Nazarkina ZhK, Lavrik OI, Khodyreva SN.
Mol Biol (Mosk). 2008 May-Jun;42(3):405-21. (REVIEW)
PMID 18702299
FEN1 is overexpressed in testis, lung and brain tumors.
Nikolova T, Christmann M, Kaina B.
Anticancer Res. 2009 Jul;29(7):2453-9.
PMID 19596913
Differential processing of leading- and lagging-strand ends at Saccharomyces cerevisiae telomeres revealed by the absence of Rad27p nuclease.
Parenteau J, Wellinger RJ.
Genetics. 2002 Dec;162(4):1583-94.
PMID 12524334
A single cleavage assay for T5 5'-->3' exonuclease: determination of the catalytic parameters forwild-type and mutant proteins.
Pickering TJ, Garforth SJ, Thorpe SJ, Sayers JR, Grasby JA.
Nucleic Acids Res. 1999 Feb 1;27(3):730-5.
PMID 9889266
Cell cycle-dependent and DNA damage-inducible nuclear localization of FEN-1 nuclease is consistent with its dual functions in DNA replication and repair.
Qiu J, Li X, Frank G, Shen B.
J Biol Chem. 2001 Feb 16;276(7):4901-8. Epub 2000 Oct 25.
PMID 11053418
Characterization of a mutant strain of Saccharomyces cerevisiae with a deletion of the RAD27 gene, a structural homolog of the RAD2 nucleotide excision repair gene.
Reagan MS, Pittenger C, Siede W, Friedberg EC.
J Bacteriol. 1995 Jan;177(2):364-71.
PMID 7814325
DNA repair in mammalian cells: Base excision repair: the long and short of it.
Robertson AB, Klungland A, Rognes T, Leiros I.
Cell Mol Life Sci. 2009 Mar;66(6):981-93. (REVIEW)
PMID 19153658
Lagging strand replication proteins in genome stability and DNA repair.
Rossi ML, Purohit V, Brandt PD, Bambara RA.
Chem Rev. 2006 Feb;106(2):453-73. (REVIEW)
PMID 16464014
Flap endonuclease 1 contributes to telomere stability.
Saharia A, Guittat L, Crocker S, Lim A, Steffen M, Kulkarni S, Stewart SA.
Curr Biol. 2008 Apr 8;18(7):496-500.
PMID 18394896
FEN1 contributes to telomere stability in ALT-positive tumor cells.
Saharia A, Stewart SA.
Oncogene. 2009 Feb 26;28(8):1162-7. Epub 2009 Jan 12.
PMID 19137021
Structural basis for recruitment of human flap endonuclease 1 to PCNA.
Sakurai S, Kitano K, Yamaguchi H, Hamada K, Okada K, Fukuda K, Uchida M, Ohtsuka E, Morioka H, Hakoshima T.
EMBO J. 2005 Feb 23;24(4):683-93. Epub 2004 Dec 16.
PMID 15616578
Human flap endonuclease I is in complex with telomerase and is required for telomerase-mediated telomere maintenance.
Sampathi S, Bhusari A, Shen B, Chai W.
J Biol Chem. 2009 Feb 6;284(6):3682-90. Epub 2008 Dec 9.
PMID 19068479
Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer.
Sato M, Girard L, Sekine I, Sunaga N, Ramirez RD, Kamibayashi C, Minna JD.
Oncogene. 2003 Oct 16;22(46):7243-6.
PMID 14562054
WRN helicase and FEN-1 form a complex upon replication arrest and together process branchmigrating DNA structures associated with the replication fork.
Sharma S, Otterlei M, Sommers JA, Driscoll HC, Dianov GL, Kao HI, Bambara RA, Brosh RM Jr.
Mol Biol Cell. 2004 Feb;15(2):734-50. Epub 2003 Dec 2.
PMID 14657243
Flap endonuclease homologs in archaebacteria exist as independent proteins.
Shen B, Qiu J, Hosfield D, Tainer JA.
Trends Biochem Sci. 1998 May;23(5):171-3. (REVIEW)
PMID 9612080
Multiple but dissectible functions of FEN-1 nucleases in nucleic acid processing, genome stability and diseases.
Shen B, Singh P, Liu R, Qiu J, Zheng L, Finger LD, Alas S.
Bioessays. 2005 Jul;27(7):717-29. (REVIEW)
PMID 15954100
Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers.
Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B.
Mol Cancer Res. 2008 Nov;6(11):1710-7.
PMID 19010819
Conditional lethality of null mutations in RTH1 that encodes the yeast counterpart of a mammalian 5'- to 3'-exonuclease required for lagging strand DNA synthesis in reconstituted systems.
Sommers CH, Miller EJ, Dujon B, Prakash S, Prakash L.
J Biol Chem. 1995 Mar 3;270(9):4193-6.
PMID 7876174
Three metal ions participate in the reaction catalyzed by T5 flap endonuclease.
Syson K, Tomlinson C, Chapados BR, Sayers JR, Tainer JA, Williams NH, Grasby JA.
J Biol Chem. 2008 Oct 17;283(42):28741-6. Epub 2008 Aug 11.
PMID 18697748
Long patch base excision repair in mammalian mitochondrial genomes.
Szczesny B, Tann AW, Longley MJ, Copeland WC, Mitra S.
J Biol Chem. 2008 Sep 26;283(39):26349-56. Epub 2008 Jul 17.
PMID 18635552
A novel mutation avoidance mechanism dependent on S. cerevisiae RAD27 is distinct from DNA mismatch repair.
Tishkoff DX, Filosi N, Gaida GM, Kolodner RD.
Cell. 1997 Jan 24;88(2):253-63.
PMID 9008166
Fen1 expression: a novel marker for cell proliferation.
Warbrick E, Coates PJ, Hall PA.
J Pathol. 1998 Nov;186(3):319-24.
PMID 10211123
Functional FEN1 polymorphisms are associated with DNA damage levels and lung cancer risk.
Yang M, Guo H, Wu C, He Y, Yu D, Zhou L, Wang F, Xu J, Tan W, Wang G, Shen B, Yuan J, Wu T, Lin D.
Hum Mutat. 2009 Sep;30(9):1320-8.
PMID 19618370
Making and breaking nucleic acids: two-Mg2+-ion catalysis and substrate specificity.
Yang W, Lee JY, Nowotny M.
Mol Cell. 2006 Apr 7;22(1):5-13. (REVIEW)
PMID 16600865
Fen1 mutations result in autoimmunity, chronic inflammation and cancers.
Zheng L, Dai H, Zhou M, Li M, Singh P, Qiu J, Tsark W, Huang Q, Kernstine K, Zhang X, Lin D, Shen B.
Nat Med. 2007 Jul;13(7):812-9. Epub 2007 Jun 24.
PMID 17589521
Novel function of the flap endonuclease 1 complex in processing stalled DNA replication forks.
Zheng L, Zhou M, Chai Q, Parrish J, Xue D, Patrick SM, Turchi JJ, Yannone SM, Chen D, Shen B.
EMBO Rep. 2005 Jan;6(1):83-9.
PMID 15592449


This paper should be referenced as such :
Finger, LD ; Shen, B
FEN1 (flap structure-specific endonuclease 1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(10):955-961.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias t0511q35q12ID1679

External links

HGNC (Hugo)FEN1   3650
Entrez_Gene (NCBI)FEN1  2237  flap structure-specific endonuclease 1
AliasesFEN-1; MF1; RAD2
GeneCards (Weizmann)FEN1
Ensembl hg19 (Hinxton)ENSG00000168496 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000168496 [Gene_View]  ENSG00000168496 [Sequence]  chr11:61792637-61797242 [Contig_View]  FEN1 [Vega]
ICGC DataPortalENSG00000168496
TCGA cBioPortalFEN1
AceView (NCBI)FEN1
Genatlas (Paris)FEN1
SOURCE (Princeton)FEN1
Genetics Home Reference (NIH)FEN1
Genomic and cartography
GoldenPath hg38 (UCSC)FEN1  -     chr11:61792637-61797242 +  11q12.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FEN1  -     11q12.2   [Description]    (hg19-Feb_2009)
GoldenPathFEN1 - 11q12.2 [CytoView hg19]  FEN1 - 11q12.2 [CytoView hg38]
Mapping of homologs : NCBIFEN1 [Mapview hg19]  FEN1 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AK301743 AK312761 BC000323 BM450370 BP244711
RefSeq transcript (Entrez)NM_004111
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)FEN1
Cluster EST : UnigeneHs.409065 [ NCBI ]
CGAP (NCI)Hs.409065
Alternative Splicing GalleryENSG00000168496
Gene ExpressionFEN1 [ NCBI-GEO ]   FEN1 [ EBI - ARRAY_EXPRESS ]   FEN1 [ SEEK ]   FEN1 [ MEM ]
Gene Expression Viewer (FireBrowse)FEN1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2237
GTEX Portal (Tissue expression)FEN1
Human Protein AtlasENSG00000168496-FEN1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP39748   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP39748  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP39748
Splice isoforms : SwissVarP39748
Domaine pattern : Prosite (Expaxy)XPG_1 (PS00841)    XPG_2 (PS00842)   
Domains : Interpro (EBI)5-3_exonuclease_C_sf    Flap_endonuc    HhH2    PIN-like_dom_sf    XPG-I_dom    XPG/Rad2    XPG_CS    XPG_DNA_repair_N   
Domain families : Pfam (Sanger)XPG_I (PF00867)    XPG_N (PF00752)   
Domain families : Pfam (NCBI)pfam00867    pfam00752   
Domain families : Smart (EMBL)HhH2 (SM00279)  XPGI (SM00484)  XPGN (SM00485)  
Conserved Domain (NCBI)FEN1
DMDM Disease mutations2237
Blocks (Seattle)FEN1
PDB (RSDB)1U7B    1UL1    3Q8K    3Q8L    3Q8M    3UVU    5E0V    5FV7    5K97    5KSE    5UM9   
PDB Europe1U7B    1UL1    3Q8K    3Q8L    3Q8M    3UVU    5E0V    5FV7    5K97    5KSE    5UM9   
PDB (PDBSum)1U7B    1UL1    3Q8K    3Q8L    3Q8M    3UVU    5E0V    5FV7    5K97    5KSE    5UM9   
PDB (IMB)1U7B    1UL1    3Q8K    3Q8L    3Q8M    3UVU    5E0V    5FV7    5K97    5KSE    5UM9   
Structural Biology KnowledgeBase1U7B    1UL1    3Q8K    3Q8L    3Q8M    3UVU    5E0V    5FV7    5K97    5KSE    5UM9   
SCOP (Structural Classification of Proteins)1U7B    1UL1    3Q8K    3Q8L    3Q8M    3UVU    5E0V    5FV7    5K97    5KSE    5UM9   
CATH (Classification of proteins structures)1U7B    1UL1    3Q8K    3Q8L    3Q8M    3UVU    5E0V    5FV7    5K97    5KSE    5UM9   
Human Protein Atlas [tissue]ENSG00000168496-FEN1 [tissue]
Peptide AtlasP39748
IPIIPI00026215   IPI01009939   
Protein Interaction databases
IntAct (EBI)P39748
Ontologies - Pathways
Ontology : AmiGOmagnesium ion binding  double-strand break repair via homologous recombination  nuclear chromosome, telomeric region  nuclear chromosome, telomeric region  DNA binding  damaged DNA binding  double-stranded DNA binding  endonuclease activity  RNA-DNA hybrid ribonuclease activity  RNA-DNA hybrid ribonuclease activity  exonuclease activity  protein binding  nucleus  nucleus  nucleoplasm  nucleolus  mitochondrion  DNA replication  DNA repair  base-excision repair  double-strand break repair  memory  double-stranded DNA exodeoxyribonuclease activity  5'-3' exonuclease activity  5'-3' exonuclease activity  UV protection  membrane  5'-flap endonuclease activity  5'-flap endonuclease activity  5'-flap endonuclease activity  5'-flap endonuclease activity  manganese ion binding  telomere maintenance via semi-conservative replication  protein-containing complex  DNA replication, removal of RNA primer  positive regulation of sister chromatid cohesion  flap endonuclease activity  flap endonuclease activity  nucleic acid phosphodiester bond hydrolysis  RNA phosphodiester bond hydrolysis, endonucleolytic  
Ontology : EGO-EBImagnesium ion binding  double-strand break repair via homologous recombination  nuclear chromosome, telomeric region  nuclear chromosome, telomeric region  DNA binding  damaged DNA binding  double-stranded DNA binding  endonuclease activity  RNA-DNA hybrid ribonuclease activity  RNA-DNA hybrid ribonuclease activity  exonuclease activity  protein binding  nucleus  nucleus  nucleoplasm  nucleolus  mitochondrion  DNA replication  DNA repair  base-excision repair  double-strand break repair  memory  double-stranded DNA exodeoxyribonuclease activity  5'-3' exonuclease activity  5'-3' exonuclease activity  UV protection  membrane  5'-flap endonuclease activity  5'-flap endonuclease activity  5'-flap endonuclease activity  5'-flap endonuclease activity  manganese ion binding  telomere maintenance via semi-conservative replication  protein-containing complex  DNA replication, removal of RNA primer  positive regulation of sister chromatid cohesion  flap endonuclease activity  flap endonuclease activity  nucleic acid phosphodiester bond hydrolysis  RNA phosphodiester bond hydrolysis, endonucleolytic  
Pathways : KEGGDNA replication    Base excision repair    Non-homologous end-joining   
REACTOMEP39748 [protein]
REACTOME PathwaysR-HSA-69166 [pathway]   
NDEx NetworkFEN1
Atlas of Cancer Signalling NetworkFEN1
Wikipedia pathwaysFEN1
Orthology - Evolution
GeneTree (enSembl)ENSG00000168496
Phylogenetic Trees/Animal Genes : TreeFamFEN1
Homologs : HomoloGeneFEN1
Homology/Alignments : Family Browser (UCSC)FEN1
Gene fusions - Rearrangements
Fusion : FusionGDB13307    13308    16787    24285   
Fusion : Fusion_HubFEN1--GDPD4    FEN1--SULF1    HS3ST4--FEN1    TMEM175--FEN1   
Fusion : QuiverFEN1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFEN1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FEN1
Exome Variant ServerFEN1
ExAC (Exome Aggregation Consortium)ENSG00000168496
GNOMAD BrowserENSG00000168496
Varsome BrowserFEN1
Genetic variants : HAPMAP2237
Genomic Variants (DGV)FEN1 [DGVbeta]
DECIPHERFEN1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFEN1 
ICGC Data PortalFEN1 
TCGA Data PortalFEN1 
Broad Tumor PortalFEN1
OASIS PortalFEN1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFEN1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DFEN1
Mutations and Diseases : HGMDFEN1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch FEN1
DgiDB (Drug Gene Interaction Database)FEN1
DoCM (Curated mutations)FEN1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)FEN1 (select a term)
NCG5 (London)FEN1
Cancer3DFEN1(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry FEN1
NextProtP39748 [Medical]
Target ValidationFEN1
Huge Navigator FEN1 [HugePedia]
snp3D : Map Gene to Disease2237
BioCentury BCIQFEN1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2237
Chemical/Pharm GKB GenePA28090
Clinical trialFEN1
canSAR (ICR)FEN1 (select the gene name)
DataMed IndexFEN1
PubMed209 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Jan 27 13:40:14 CET 2020

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us