FEN1

PDB 1ul1
FEN1
Identificadores
Símbolo	FEN1
Símbolos alt.	Flap endonuclease 1, flap structure-specific endonuclease 1, FEN-1, MF1, RAD2
Entrez	2237
RefSeq	NP_004102.1
UniProt	P39748
Outros datos
Locus	Cr. 11 :(61.79 – 61.8 Mb)

FEN1 (Flap endonuclease 1, endonuclease flap 1 ou endonuclease de solapa 1), tamén chamada endonuclease específica da estrutura de solapa 1 (flap structure-specific endonuclease 1), é un encima que nos humanos está codificado polo xene FEN1 do cromosoma 11.^[1][2]

Función

A proteína codificada por este xene elimina as solapas ou flaps 5' colgantes (ou curtas seccións de ADN de febra simple que sobresaen e quedan "colgando" porque as súas bases nucleotídicas non poden unirse ás súas bases complementarias) formadas na reparación do ADN e procesan os extremos 5' dos fragmentos de Okazaki na febra retardada durante a síntese de ADN. A interacción física directa entre esta proteína e a endonuclease AP 1 durante a reparación por escisión de bases de parche longo fai que se produza unha carga ordenada de proteínas sobre o substrato, pasando así o substrato dun encima a outro. A proteína é un membro da familia de endonucleases XPG/RAD2 e é unha das dez proteínas esenciais para a replicación do ADN en sistemas libres de células. A estrutura secundaria do ADN pode inhibir o procesamento das solapas onde hai certas repeticións de trinucleótido de maneira dependente da lonxitude ao ocultar o extremo 5' da solapa, que é necesario para a unión e a clivaxe pola proteína codificada por este xene. Por tanto, a estrutura secundaria pode impedir a función protectora desta proteína, orixinando expansións de trinucleótidos específicos de sitio.^[2]

Interaccións

A endonuclease específica de estrutura flap 1 (FEN1) presenta interaccións con:

• APEX1,^[3]
• BLM^[4]
• CDK2,^[5]
• CCNA2,^[5]
• EP300,^[6]
• HNRNPA1,^[7]
• PCNA,^{[3][5][6][8][9][10][11]} e
• WRN.^[4][12]

Sobreexpresión de FEN1 en cancros

A FEN1 sobreexprésase na maioría dos cancros de mama,^[13] próstata,^[14] estómago,^[15][16] neuroblastomas,^[17] pancreáticos,^[18] e de pulmón.^[19]

A FEN1 é un encima esencial nunha vía de reparacións inexacta de roturas de dobre febra no ADN chamada unión de extremos alternativa dependente de microhomoloxía ou unión de extremos mediada por microhomoloxía (MMEJ).^[20] A MMEJ sempre implica polo menos unha pequena deleción, polo que é unha vía mutaxénica.^[21] Outras vías poden tamén reparar roturas de dobre febra no ADN, incluíndo a vía menos inexacta da unión de extremos non homólogos (NHEJ) e vías exactas que usan a reparación recombinacional homóloga (HRR).^[22] Varios factores determinan que vía se usará para reparar as roturas de dobre febra do ADN.^[21] Cando a FEN1 se sobreexpresa (e isto ocorre cando o seu promotor é hipometilado^[13]) a vía moi inexacta MMEJ pode ser favorecida, causando un maior grao de mutación e un incremento do risco de cancro.

Os cancros son a miúdo deficientes na expresión dun ou máis xenes de reparación do ADN, pero a sobreexpresión dun xene de reparación do ADN é infrecuente no cancro.^[23][23] A reparación MMEJ mediada pola FEN1 é moi inexacta, polo que neste caso, a sobreexpresión, en vez da subexpresión, conduce ao cancro.

Notas

1. Hiraoka LR, Harrington JJ, Gerhard DS, Lieber MR, Hsieh CL (Jul 1995). "Sequence of human FEN-1, a structure-specific endonuclease, and chromosomal localization of the gene (FEN1) in mouse and human". Genomics 25 (1): 220–5. PMID 7774922. doi:10.1016/0888-7543(95)80129-A. 
2. "Entrez Gene: FEN1 flap structure-specific endonuclease 1". 
3. Dianova II, Bohr VA, Dianov GL (Oct 2001). "Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair". Biochemistry 40 (42): 12639–44. PMID 11601988. doi:10.1021/bi011117i. 
4. Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM (Mar 2004). "Stimulation of flap endonuclease-1 by the Bloom's syndrome protein". J. Biol. Chem. 279 (11): 9847–56. PMID 14688284. doi:10.1074/jbc.M309898200. 
5. Henneke G, Koundrioukoff S, Hübscher U (Jul 2003). "Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation". Oncogene 22 (28): 4301–13. PMID 12853968. doi:10.1038/sj.onc.1206606. 
6. Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hübscher U, Hottiger MO (Jun 2001). "Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300". Mol. Cell 7 (6): 1221–31. PMID 11430825. doi:10.1016/s1097-2765(01)00272-6. 
7. Chai Q, Zheng L, Zhou M, Turchi JJ, Shen B (Dec 2003). "Interaction and stimulation of human FEN-1 nuclease activities by heterogeneous nuclear ribonucleoprotein A1 in alpha-segment processing during Okazaki fragment maturation". Biochemistry 42 (51): 15045–52. PMID 14690413. doi:10.1021/bi035364t. 
8. Jónsson ZO, Hindges R, Hübscher U (Apr 1998). "Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen". EMBO J. 17 (8): 2412–25. PMC 1170584. PMID 9545252. doi:10.1093/emboj/17.8.2412. 
9. Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS (Sep 1997). "The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNA-binding regions of FEN-1 and cyclin-dependent kinase inhibitor p21". J. Biol. Chem. 272 (39): 24522–9. PMID 9305916. doi:10.1074/jbc.272.39.24522. 
10. Chen U, Chen S, Saha P, Dutta A (Oct 1996). "p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex". Proc. Natl. Acad. Sci. U.S.A. 93 (21): 11597–602. PMC 38103. PMID 8876181. doi:10.1073/pnas.93.21.11597. 
11. Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y (Jan 2001). "p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues". Oncogene 20 (4): 484–9. PMID 11313979. doi:10.1038/sj.onc.1204113. 
12. Brosh RM, von Kobbe C, Sommers JA, Karmakar P, Opresko PL, Piotrowski J, Dianova I, Dianov GL, Bohr VA (Oct 2001). "Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity". EMBO J. 20 (20): 5791–801. PMC 125684. PMID 11598021. doi:10.1093/emboj/20.20.5791. 
13. Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B (2008). "Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers". Mol. Cancer Res. 6 (11): 1710–7. PMC 2948671. PMID 19010819. doi:10.1158/1541-7786.MCR-08-0269. 
14. Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS (2006). "Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score". BJU Int. 98 (2): 445–51. PMID 16879693. doi:10.1111/j.1464-410X.2006.06224.x. 
15. Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Yoo HS, Kim YS, Kim JG, Kim NS (2005). "Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells". Clin. Cancer Res. 11 (2 Pt 1): 473–82. PMID 15701830. 
16. Wang K, Xie C, Chen D (2014). "Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis". Int. J. Mol. Med. 33 (5): 1268–74. PMID 24590400. doi:10.3892/ijmm.2014.1682. 
17. Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A (2005). "Genome-wide analysis of gene expression in neuroblastomas detected by mass screening". Cancer Lett. 225 (1): 111–20. PMID 15922863. doi:10.1016/j.canlet.2004.10.035. 
18. 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 (2003). "Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays". Am. J. Pathol. 162 (4): 1151–62. PMC 1851213. PMID 12651607. doi:10.1016/S0002-9440(10)63911-9. 
19. Nikolova T, Christmann M, Kaina B (2009). "FEN1 is overexpressed in testis, lung and brain tumors". Anticancer Res. 29 (7): 2453–9. PMID 19596913. 
20. Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis 6: e1697. PMC 4385936. PMID 25789972. doi:10.1038/cddis.2015.58. 
21. Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA (2005). "Modulation of DNA end joining by nuclear proteins". J. Biol. Chem. 280 (36): 31442–9. PMID 16012167. doi:10.1074/jbc.M503776200. 
22. Ottaviani D, LeCain M, Sheer D (2014). "The role of microhomology in genomic structural variation". Trends Genet. 30 (3): 85–94. PMID 24503142. doi:10.1016/j.tig.2014.01.001. 
23. Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer

Véxase tamén

Outros artigos

• Finger LD, Blanchard MS, Theimer CA, Sengerová B, Singh P, Chavez V, Liu F, Grasby JA, Shen B (2009). "The 3'-flap pocket of human flap endonuclease 1 is critical for substrate binding and catalysis.". J. Biol. Chem. 284 (33): 22184–94. PMC 2755943. PMID 19525235. doi:10.1074/jbc.M109.015065. 
• Kemeny MM, Alava G, Oliver JM (1993). "Improving responses in hepatomas with circadian-patterned hepatic artery infusions of recombinant interleukin-2.". J. Immunother. 12 (4): 219–23. PMID 1477073. doi:10.1097/00002371-199211000-00001. 
• Li X, Li J, Harrington J, Lieber MR, Burgers PM (1995). "Lagging strand DNA synthesis at the eukaryotic replication fork involves binding and stimulation of FEN-1 by proliferating cell nuclear antigen.". J. Biol. Chem. 270 (38): 22109–12. PMID 7673186. doi:10.1074/jbc.270.38.22109. 
• Robins P, Pappin DJ, Wood RD, Lindahl T (1994). "Structural and functional homology between mammalian DNase IV and the 5'-nuclease domain of Escherichia coli DNA polymerase I.". J. Biol. Chem. 269 (46): 28535–8. PMID 7961795. 
• Murray JM, Tavassoli M, al-Harithy R, Sheldrick KS, Lehmann AR, Carr AM, Watts FZ (1994). "Structural and functional conservation of the human homolog of the Schizosaccharomyces pombe rad2 gene, which is required for chromosome segregation and recovery from DNA damage.". Mol. Cell. Biol. 14 (7): 4878–88. PMC 358860. PMID 8007985. 
• Harrington JJ, Lieber MR (1994). "The characterization of a mammalian DNA structure-specific endonuclease.". EMBO J. 13 (5): 1235–46. PMC 394933. PMID 8131753. 
• Shen B, Nolan JP, Sklar LA, Park MS (1996). "Essential amino acids for substrate binding and catalysis of human flap endonuclease 1.". J. Biol. Chem. 271 (16): 9173–6. PMID 8621570. doi:10.1074/jbc.271.16.9173. 
• Chen U, Chen S, Saha P, Dutta A (1996). "p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex.". Proc. Natl. Acad. Sci. U.S.A. 93 (21): 11597–602. PMC 38103. PMID 8876181. doi:10.1073/pnas.93.21.11597. 
• Warbrick E, Lane DP, Glover DM, Cox LS (1997). "Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair.". Oncogene 14 (19): 2313–21. PMID 9178907. doi:10.1038/sj.onc.1201072. 
• Klungland A, Lindahl T (1997). "Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1).". EMBO J. 16 (11): 3341–8. PMC 1169950. PMID 9214649. doi:10.1093/emboj/16.11.3341. 
• Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS (1997). "The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNA-binding regions of FEN-1 and cyclin-dependent kinase inhibitor p21.". J. Biol. Chem. 272 (39): 24522–9. PMID 9305916. doi:10.1074/jbc.272.39.24522. 
• Stöhr H, Marquardt A, Rivera A, Cooper PR, Nowak NJ, Shows TB, Gerhard DS, Weber BH (1998). "A gene map of the Best's vitelliform macular dystrophy region in chromosome 11q12-q13.1.". Genome Res. 8 (1): 48–56. PMC 310689. PMID 9445487. doi:10.1101/gr.8.1.48. 
• Jónsson ZO, Hindges R, Hübscher U (1998). "Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen.". EMBO J. 17 (8): 2412–25. PMC 1170584. PMID 9545252. doi:10.1093/emboj/17.8.2412. 
• Warbrick E, Heatherington W, Lane DP, Glover DM (1998). "PCNA binding proteins in Drosophila melanogaster : the analysis of a conserved PCNA binding domain.". Nucleic Acids Res. 26 (17): 3925–32. PMC 147798. PMID 9705499. doi:10.1093/nar/26.17.3925. 
• Hosfield DJ, Mol CD, Shen B, Tainer JA (1998). "Structure of the DNA repair and replication endonuclease and exonuclease FEN-1: coupling DNA and PCNA binding to FEN-1 activity.". Cell 95 (1): 135–46. PMID 9778254. doi:10.1016/S0092-8674(00)81789-4. 
• Dianov GL, Jensen BR, Kenny MK, Bohr VA (1999). "Replication protein A stimulates proliferating cell nuclear antigen-dependent repair of abasic sites in DNA by human cell extracts.". Biochemistry 38 (34): 11021–5. PMID 10460157. doi:10.1021/bi9908890. 
• Greene AL, Snipe JR, Gordenin DA, Resnick MA (1999). "Functional analysis of human FEN1 in Saccharomyces cerevisiae and its role in genome stability.". Hum. Mol. Genet. 8 (12): 2263–73. PMID 10545607. doi:10.1093/hmg/8.12.2263. 
• Matsumoto Y, Kim K, Hurwitz J, Gary R, Levin DS, Tomkinson AE, Park MS (1999). "Reconstitution of proliferating cell nuclear antigen-dependent repair of apurinic/apyrimidinic sites with purified human proteins.". J. Biol. Chem. 274 (47): 33703–8. PMID 10559261. doi:10.1074/jbc.274.47.33703. 
• Spiro C, Pelletier R, Rolfsmeier ML, Dixon MJ, Lahue RS, Gupta G, Park MS, Chen X, Mariappan SV, McMurray CT (2000). "Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats.". Mol. Cell 4 (6): 1079–85. PMID 10635332. doi:10.1016/S1097-2765(00)80236-1. 
• Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hübscher U, Hottiger MO (2001). "Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300.". Mol. Cell 7 (6): 1221–31. PMID 11430825. doi:10.1016/S1097-2765(01)00272-6. 
• Caldwell RB, Braselmann H, Schoetz U, Heuer S, Scherthan H, Zitzelsberger H (July 4, 2016). "Positive Cofactor 4 (PC4) is critical for DNA repair pathway re-routing in DT40 cells.". Sci Rep. PMC 4931448. PMID 27374870. doi:10.1038/srep28890.