ID XPF_HUMAN Reviewed; 916 AA. AC Q92889; A5PKV6; A8K111; O00140; Q8TD83; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 05-MAY-2009, sequence version 3. DT 27-MAR-2024, entry version 225. DE RecName: Full=DNA repair endonuclease XPF; DE EC=3.1.-.- {ECO:0000269|PubMed:10413517}; DE AltName: Full=DNA excision repair protein ERCC-4 {ECO:0000303|PubMed:8887684}; DE AltName: Full=DNA repair protein complementing XP-F cells {ECO:0000303|PubMed:8797827}; DE AltName: Full=Xeroderma pigmentosum group F-complementing protein {ECO:0000303|PubMed:8797827}; GN Name=ERCC4 {ECO:0000303|PubMed:8887684, ECO:0000312|HGNC:HGNC:3436}; GN Synonyms=ERCC11, XPF {ECO:0000303|PubMed:8887684}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8887684; DOI=10.1128/mcb.16.11.6553; RA Brookman K.W., Lamerdin J.E., Thelen M.P., Hwang M., Reardon J.T., RA Sancar A., Zhou Z.-Q., Walter C.A., Parris C.N., Thompson L.H.; RT "ERCC4 (XPF) encodes a human nucleotide excision repair protein with RT eukaryotic recombination homologs."; RL Mol. Cell. Biol. 16:6553-6562(1996). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-168; SER-379; GLN-415; RP PRO-662; THR-706; VAL-873 AND GLY-875. RG NIEHS SNPs program; RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLN-415. RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M., RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., RA Myers R.M., Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 7-916 (ISOFORM 1), FUNCTION, VARIANT ASP-703, RP AND VARIANT XP-F TRP-799. RC TISSUE=Fibroblast; RX PubMed=8797827; DOI=10.1016/s0092-8674(00)80155-5; RA Sijbers A.M., de Laat W.L., Ariza R.R., Biggerstaff M., Wei Y.-F., RA Moggs J.G., Carter K.C., Shell B.K., Evans E., de Jong M.C., Rademakers S., RA de Rooij J., Jaspers N.G.J., Hoeijmakers J.H.J., Wood R.D.; RT "Xeroderma pigmentosum group F caused by a defect in a structure-specific RT DNA repair endonuclease."; RL Cell 86:811-822(1996). RN [7] RP REVIEW ON VARIANTS XP-F. RX PubMed=10447254; RX DOI=10.1002/(sici)1098-1004(1999)14:1<9::aid-humu2>3.0.co;2-6; RA Cleaver J.E., Thompson L.H., Richardson A.S., States J.C.; RT "A summary of mutations in the UV-sensitive disorders: xeroderma RT pigmentosum, Cockayne syndrome, and trichothiodystrophy."; RL Hum. Mutat. 14:9-22(1999). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND INTERACTION WITH ERCC1. RX PubMed=10413517; DOI=10.1021/bi990591+; RA McCutchen-Maloney S.L., Giannecchini C.A., Hwang M.H., Thelen M.P.; RT "Domain mapping of the DNA binding, endonuclease, and ERCC1 binding RT properties of the human DNA repair protein XPF."; RL Biochemistry 38:9417-9425(1999). RN [9] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=11790111; DOI=10.1021/bi011614z; RA Kumaresan K.R., Hwang M., Thelen M.P., Lambert M.W.; RT "Contribution of XPF functional domains to the 5' and 3' incisions produced RT at the site of a psoralen interstrand cross-link."; RL Biochemistry 41:890-896(2002). RN [10] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SLX4. RX PubMed=19596235; DOI=10.1016/j.cell.2009.06.030; RA Svendsen J.M., Smogorzewska A., Sowa M.E., O'Connell B.C., Gygi S.P., RA Elledge S.J., Harper J.W.; RT "Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is RT required for DNA repair."; RL Cell 138:63-77(2009). RN [11] RP INTERACTION WITH SLX4. RX PubMed=19596236; DOI=10.1016/j.cell.2009.06.029; RA Fekairi S., Scaglione S., Chahwan C., Taylor E.R., Tissier A., Coulon S., RA Dong M.-Q., Ruse C., Yates J.R. III, Russell P., Fuchs R.P., McGowan C.H., RA Gaillard P.-H.L.; RT "Human SLX4 is a Holliday junction resolvase subunit that binds multiple RT DNA repair/recombination endonucleases."; RL Cell 138:78-89(2009). RN [12] RP INTERACTION WITH SLX4. RX PubMed=19595721; DOI=10.1016/j.molcel.2009.06.020; RA Munoz I.M., Hain K., Declais A.-C., Gardiner M., Toh G.W., RA Sanchez-Pulido L., Heuckmann J.M., Toth R., Macartney T., Eppink B., RA Kanaar R., Ponting C.P., Lilley D.M.J., Rouse J.; RT "Coordination of structure-specific nucleases by human SLX4/BTBD12 is RT required for DNA repair."; RL Mol. Cell 35:116-127(2009). RN [13] RP INTERACTION WITH SLX4. RX PubMed=19595722; DOI=10.1016/j.molcel.2009.06.019; RA Andersen S.L., Bergstralh D.T., Kohl K.P., LaRocque J.R., Moore C.B., RA Sekelsky J.; RT "Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA RT structure-specific endonucleases in DNA repair and recombination."; RL Mol. Cell 35:128-135(2009). RN [14] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-289, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [17] RP INTERACTION WITH ERCC1 AND SLX4. RX PubMed=25538220; DOI=10.15252/embj.201489184; RA Perez-Oliva A.B., Lachaud C., Szyniarowski P., Munoz I., Macartney T., RA Hickson I., Rouse J., Alessi D.R.; RT "USP45 deubiquitylase controls ERCC1-XPF endonuclease-mediated DNA damage RT responses."; RL EMBO J. 34:326-343(2015). RN [18] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-500, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [19] RP FUNCTION, INTERACTION WITH ERCC1, ACETYLATION AT LYS-911, AND MUTAGENESIS RP OF LYS-911. RX PubMed=32034146; DOI=10.1038/s41467-020-14564-x; RA Wang J., He H., Chen B., Jiang G., Cao L., Jiang H., Zhang G., Chen J., RA Huang J., Yang B., Zhou C., Liu T.; RT "Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and RT activation."; RL Nat. Commun. 11:786-786(2020). RN [20] {ECO:0007744|PDB:2A1J} RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 848-909 IN COMPLEX WITH ERCC1, RP DNA-BINDING, DOMAINS, AND SUBUNIT. RX PubMed=16076955; DOI=10.1073/pnas.0504341102; RA Tsodikov O.V., Enzlin J.H., Scharer O.D., Ellenberger T.; RT "Crystal structure and DNA binding functions of ERCC1, a subunit of the DNA RT structure-specific endonuclease XPF-ERCC1."; RL Proc. Natl. Acad. Sci. U.S.A. 102:11236-11241(2005). RN [21] {ECO:0007744|PDB:1Z00} RP STRUCTURE BY NMR OF 834-916 IN COMPLEX WITH ERCC1, AND SUBUNIT. RX PubMed=16338413; DOI=10.1016/j.str.2005.08.014; RA Tripsianes K., Folkers G., Ab E., Das D., Odijk H., Jaspers N.G., RA Hoeijmakers J.H., Kaptein R., Boelens R.; RT "The structure of the human ERCC1/XPF interaction domains reveals a RT complementary role for the two proteins in nucleotide excision repair."; RL Structure 13:1849-1858(2005). RN [22] RP VARIANT SER-379. RX PubMed=9485007; RA Shen M.R., Jones I.M., Mohrenweiser H.; RT "Nonconservative amino acid substitution variants exist at polymorphic RT frequency in DNA repair genes in healthy humans."; RL Cancer Res. 58:604-608(1998). RN [23] RP VARIANTS XP-F MET-225; TRP-454; GLN-490; LYS-502; ARG-513; THR-529; RP ALA-567; 605-VAL--GLY-611 DEL AND PRO-608. RX PubMed=9580660; DOI=10.1093/hmg/7.6.969; RA Matsumura Y., Nishigori C., Yagi T., Imamura S., Takebe H.; RT "Characterization of molecular defects in Xeroderma pigmentosum group F in RT relation to its clinically mild symptoms."; RL Hum. Mol. Genet. 7:969-974(1998). RN [24] RP VARIANT XP-F TRP-799. RX PubMed=9579555; DOI=10.1046/j.1523-1747.1998.00171.x; RA Sijbers A.M., van Voorst Vader P.C., Snoek J.W., Raams A., Jaspers N.G.J., RA Kleijer W.J.; RT "Homozygous R788W point mutation in the XPF gene of a patient with RT xeroderma pigmentosum and late-onset neurologic disease."; RL J. Invest. Dermatol. 110:832-836(1998). RN [25] RP VARIANTS GLN-415; THR-576; THR-717 AND GLY-875. RX PubMed=10479728; DOI=10.1016/s1383-5726(99)00008-4; RA Fan F., Liu C., Tavare S., Arnheim N.; RT "Polymorphisms in the human DNA repair gene XPF."; RL Mutat. Res. 406:115-120(1999). RN [26] RP VARIANT XFEPS PRO-153. RX PubMed=17183314; DOI=10.1038/nature05456; RA Niedernhofer L.J., Garinis G.A., Raams A., Lalai A.S., Robinson A.R., RA Appeldoorn E., Odijk H., Oostendorp R., Ahmad A., van Leeuwen W., RA Theil A.F., Vermeulen W., van der Horst G.T.J., Meinecke P., Kleijer W.J., RA Vijg J., Jaspers N.G.J., Hoeijmakers J.H.J.; RT "A new progeroid syndrome reveals that genotoxic stress suppresses the RT somatotroph axis."; RL Nature 444:1038-1043(2006). RN [27] RP VARIANTS FANCQ PRO-230 AND SER-689. RX PubMed=23623386; DOI=10.1016/j.ajhg.2013.04.002; RA Bogliolo M., Schuster B., Stoepker C., Derkunt B., Su Y., Raams A., RA Trujillo J.P., Minguillon J., Ramirez M.J., Pujol R., Casado J.A., RA Banos R., Rio P., Knies K., Zuniga S., Benitez J., Bueren J.A., RA Jaspers N.G., Schaerer O.D., de Winter J.P., Schindler D., Surralles J.; RT "Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause RT Fanconi anemia."; RL Am. J. Hum. Genet. 92:800-806(2013). RN [28] RP VARIANTS XPF/CS ARG-236 AND TRP-589. RX PubMed=23623389; DOI=10.1016/j.ajhg.2013.04.007; RA Kashiyama K., Nakazawa Y., Pilz D.T., Guo C., Shimada M., Sasaki K., RA Fawcett H., Wing J.F., Lewin S.O., Carr L., Li T.S., Yoshiura K., Utani A., RA Hirano A., Yamashita S., Greenblatt D., Nardo T., Stefanini M., RA McGibbon D., Sarkany R., Fassihi H., Takahashi Y., Nagayama Y., RA Mitsutake N., Lehmann A.R., Ogi T.; RT "Malfunction of nuclease ERCC1-XPF results in diverse clinical RT manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and RT Fanconi anemia."; RL Am. J. Hum. Genet. 92:807-819(2013). RN [29] RP VARIANTS CYS-150; HIS-267 AND ALA-621, VARIANTS FANCQ SER-689 AND PHE-786, RP CHARACTERIZATION OF VARIANT CYS-150, CHARACTERIZATION OF VARIANTS FANCQ RP SER-689 AND PHE-786, AND FUNCTION. RX PubMed=24027083; DOI=10.1002/humu.22438; RA Osorio A., Bogliolo M., Fernandez V., Barroso A., de la Hoya M., Caldes T., RA Lasa A., Ramon y Cajal T., Santamarina M., Vega A., Quiles F., Lazaro C., RA Diez O., Fernandez D., Gonzalez-Sarmiento R., Duran M., Piqueras J.F., RA Marin M., Pujol R., Surralles J., Benitez J.; RT "Evaluation of rare variants in the new fanconi anemia gene ERCC4 (FANCQ) RT as familial breast/ovarian cancer susceptibility alleles."; RL Hum. Mutat. 34:1615-1618(2013). CC -!- FUNCTION: Catalytic component of a structure-specific DNA repair CC endonuclease responsible for the 5-prime incision during DNA repair, CC and which is essential for nucleotide excision repair (NER) and CC interstrand cross-link (ICL) repair. {ECO:0000269|PubMed:10413517, CC ECO:0000269|PubMed:11790111, ECO:0000269|PubMed:19596235, CC ECO:0000269|PubMed:24027083, ECO:0000269|PubMed:32034146, CC ECO:0000269|PubMed:8797827}. CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:10413517}; CC -!- SUBUNIT: Heterodimer composed of ERCC1 and ERCC4/XPF (PubMed:10413517, CC PubMed:25538220, PubMed:32034146, PubMed:16076955, PubMed:16338413). CC Interacts with SLX4/BTBD12; this interaction is direct and links the CC ERCC1-ERCC4/XPF complex to SLX4, which may coordinate the action of the CC structure-specific endonuclease during DNA repair (PubMed:19596235, CC PubMed:19596236, PubMed:25538220, PubMed:19595721, PubMed:19595722). CC {ECO:0000269|PubMed:10413517, ECO:0000269|PubMed:16076955, CC ECO:0000269|PubMed:16338413, ECO:0000269|PubMed:19595721, CC ECO:0000269|PubMed:19595722, ECO:0000269|PubMed:19596235, CC ECO:0000269|PubMed:19596236, ECO:0000269|PubMed:25538220, CC ECO:0000269|PubMed:32034146}. CC -!- INTERACTION: CC Q92889; P07992: ERCC1; NbExp=13; IntAct=EBI-2370770, EBI-750962; CC Q92889; Q92889: ERCC4; NbExp=2; IntAct=EBI-2370770, EBI-2370770; CC Q92889; Q8IY92: SLX4; NbExp=10; IntAct=EBI-2370770, EBI-2370740; CC Q92889; O75410-7: TACC1; NbExp=3; IntAct=EBI-2370770, EBI-12007872; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:19596235}. Chromosome CC {ECO:0000269|PubMed:11790111}. Note=Localizes to sites of DNA damage. CC {ECO:0000269|PubMed:11790111}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q92889-1; Sequence=Displayed; CC Name=2; CC IsoId=Q92889-2; Sequence=VSP_056341, VSP_056342; CC -!- PTM: Acetylation at Lys-911 by KAT5 promotes interaction with ERCC1 by CC disrupting a salt bridge between Glu-907 and Lys-911, thereby exposing CC a second binding site for ERCC1 (PubMed:32034146). Deacetylated by CC SIRT1 (PubMed:32034146). {ECO:0000269|PubMed:32034146}. CC -!- DISEASE: Xeroderma pigmentosum complementation group F (XP-F) CC [MIM:278760]: An autosomal recessive pigmentary skin disorder CC characterized by solar hypersensitivity of the skin, high CC predisposition for developing cancers on areas exposed to sunlight and, CC in some cases, neurological abnormalities. The skin develops marked CC freckling and other pigmentation abnormalities. XP-F patients show a CC mild phenotype. {ECO:0000269|PubMed:10447254, CC ECO:0000269|PubMed:8797827, ECO:0000269|PubMed:9579555, CC ECO:0000269|PubMed:9580660}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: XFE progeroid syndrome (XFEPS) [MIM:610965]: A syndrome CC characterized by aged bird-like facies, lack of subcutaneous fat, CC dwarfism, cachexia and microcephaly. Additional features include sun- CC sensitivity from birth, learning disabilities, hearing loss, and visual CC impairment. {ECO:0000269|PubMed:17183314}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- DISEASE: Xeroderma pigmentosum type F/Cockayne syndrome (XPF/CS) CC [MIM:278760]: A variant form of Cockayne syndrome, a disorder CC characterized by growth retardation, microcephaly, impairment of CC nervous system development, pigmentary retinopathy, peculiar facies, CC and progeria together with abnormal skin photosensitivity. Cockayne CC syndrome dermatological features are milder than those in xeroderma CC pigmentosum and skin cancers are not found in affected individuals. CC XPF/CS patients, however, present with severe skin phenotypes, CC including severe photosensitivity, abnormal skin pigmentation, and skin CC cancer predisposition. {ECO:0000269|PubMed:23623389}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Fanconi anemia complementation group Q (FANCQ) [MIM:615272]: A CC disorder affecting all bone marrow elements and resulting in anemia, CC leukopenia and thrombopenia. It is associated with cardiac, renal and CC limb malformations, dermal pigmentary changes, and a predisposition to CC the development of malignancies. At the cellular level it is associated CC with hypersensitivity to DNA-damaging agents, chromosomal instability CC (increased chromosome breakage) and defective DNA repair. CC {ECO:0000269|PubMed:23623386, ECO:0000269|PubMed:24027083}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the XPF family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB07689.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/299/XPF"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/ercc4/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L77890; AAB50174.1; -; Genomic_DNA. DR EMBL; AF491814; AAL91593.1; -; Genomic_DNA. DR EMBL; AK289726; BAF82415.1; -; mRNA. DR EMBL; AC010401; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC142631; AAI42632.1; -; mRNA. DR EMBL; U64315; AAB07689.1; ALT_INIT; mRNA. DR CCDS; CCDS32390.1; -. [Q92889-1] DR RefSeq; NP_005227.1; NM_005236.2. [Q92889-1] DR PDB; 1Z00; NMR; -; B=834-916. DR PDB; 2A1J; X-ray; 2.70 A; A=848-909. DR PDB; 2AQ0; NMR; -; A/B=834-916. DR PDB; 2KN7; NMR; -; A/D=842-908. DR PDB; 2MUT; NMR; -; B=834-916. DR PDB; 6SXA; EM; 3.60 A; F=1-916. DR PDB; 6SXB; EM; 7.90 A; F=1-916. DR PDBsum; 1Z00; -. DR PDBsum; 2A1J; -. DR PDBsum; 2AQ0; -. DR PDBsum; 2KN7; -. DR PDBsum; 2MUT; -. DR PDBsum; 6SXA; -. DR PDBsum; 6SXB; -. DR AlphaFoldDB; Q92889; -. DR BMRB; Q92889; -. DR EMDB; EMD-10337; -. DR EMDB; EMD-10338; -. DR SMR; Q92889; -. DR BioGRID; 108384; 287. DR ComplexPortal; CPX-478; ERCC1-XPF endonuclease complex. DR CORUM; Q92889; -. DR DIP; DIP-42006N; -. DR IntAct; Q92889; 29. DR MINT; Q92889; -. DR STRING; 9606.ENSP00000310520; -. DR BindingDB; Q92889; -. DR ChEMBL; CHEMBL3883316; -. DR iPTMnet; Q92889; -. DR MetOSite; Q92889; -. DR PhosphoSitePlus; Q92889; -. DR BioMuta; ERCC4; -. DR DMDM; 229463004; -. DR EPD; Q92889; -. DR jPOST; Q92889; -. DR MassIVE; Q92889; -. DR MaxQB; Q92889; -. DR PaxDb; 9606-ENSP00000310520; -. DR PeptideAtlas; Q92889; -. DR ProteomicsDB; 722; -. DR ProteomicsDB; 75575; -. [Q92889-1] DR Pumba; Q92889; -. DR Antibodypedia; 24811; 603 antibodies from 32 providers. DR DNASU; 2072; -. DR Ensembl; ENST00000311895.8; ENSP00000310520.7; ENSG00000175595.16. [Q92889-1] DR Ensembl; ENST00000575156.5; ENSP00000459933.1; ENSG00000175595.16. [Q92889-2] DR GeneID; 2072; -. DR KEGG; hsa:2072; -. DR MANE-Select; ENST00000311895.8; ENSP00000310520.7; NM_005236.3; NP_005227.1. DR UCSC; uc002dce.3; human. [Q92889-1] DR AGR; HGNC:3436; -. DR CTD; 2072; -. DR DisGeNET; 2072; -. DR GeneCards; ERCC4; -. DR GeneReviews; ERCC4; -. DR HGNC; HGNC:3436; ERCC4. DR HPA; ENSG00000175595; Tissue enhanced (skeletal). DR MalaCards; ERCC4; -. DR MIM; 133520; gene. DR MIM; 278760; phenotype. DR MIM; 610965; phenotype. DR MIM; 615272; phenotype. DR neXtProt; NX_Q92889; -. DR OpenTargets; ENSG00000175595; -. DR Orphanet; 90321; Cockayne syndrome type 1. DR Orphanet; 84; Fanconi anemia. DR Orphanet; 910; Xeroderma pigmentosum. DR Orphanet; 220295; Xeroderma pigmentosum-Cockayne syndrome complex. DR PharmGKB; PA27850; -. DR VEuPathDB; HostDB:ENSG00000175595; -. DR eggNOG; KOG0442; Eukaryota. DR GeneTree; ENSGT00390000004394; -. DR HOGENOM; CLU_002265_0_0_1; -. DR InParanoid; Q92889; -. DR OMA; THILDIM; -. DR OrthoDB; 277005at2759; -. DR PhylomeDB; Q92889; -. DR TreeFam; TF101234; -. DR PathwayCommons; Q92889; -. DR Reactome; R-HSA-5685938; HDR through Single Strand Annealing (SSA). DR Reactome; R-HSA-5696395; Formation of Incision Complex in GG-NER. DR Reactome; R-HSA-5696400; Dual Incision in GG-NER. DR Reactome; R-HSA-6782135; Dual incision in TC-NER. DR Reactome; R-HSA-6783310; Fanconi Anemia Pathway. DR SignaLink; Q92889; -. DR SIGNOR; Q92889; -. DR BioGRID-ORCS; 2072; 119 hits in 1164 CRISPR screens. DR EvolutionaryTrace; Q92889; -. DR GeneWiki; ERCC4; -. DR GenomeRNAi; 2072; -. DR Pharos; Q92889; Tbio. DR PRO; PR:Q92889; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q92889; Protein. DR Bgee; ENSG00000175595; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 158 other cell types or tissues. DR ExpressionAtlas; Q92889; baseline and differential. DR Genevisible; Q92889; HS. DR GO; GO:0000781; C:chromosome, telomeric region; IDA:UniProtKB. DR GO; GO:0070522; C:ERCC4-ERCC1 complex; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0000109; C:nucleotide-excision repair complex; IDA:MGI. DR GO; GO:0000110; C:nucleotide-excision repair factor 1 complex; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0003684; F:damaged DNA binding; IMP:UniProtKB. DR GO; GO:0004520; F:DNA endonuclease activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:1990841; F:promoter-specific chromatin binding; IEA:Ensembl. DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0000014; F:single-stranded DNA endodeoxyribonuclease activity; IBA:GO_Central. DR GO; GO:0001094; F:TFIID-class transcription factor complex binding; IEA:Ensembl. DR GO; GO:0034644; P:cellular response to UV; IDA:UniProtKB. DR GO; GO:0006281; P:DNA repair; IMP:UniProtKB. DR GO; GO:0000724; P:double-strand break repair via homologous recombination; IMP:UniProtKB. DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; IMP:BHF-UCL. DR GO; GO:1905768; P:negative regulation of double-stranded telomeric DNA binding; IDA:BHF-UCL. DR GO; GO:1905765; P:negative regulation of protection from non-homologous end joining at telomere; IMP:BHF-UCL. DR GO; GO:0032205; P:negative regulation of telomere maintenance; IMP:UniProtKB. DR GO; GO:1904357; P:negative regulation of telomere maintenance via telomere lengthening; IDA:BHF-UCL. DR GO; GO:0006289; P:nucleotide-excision repair; IDA:UniProtKB. DR GO; GO:1901255; P:nucleotide-excision repair involved in interstrand cross-link repair; IDA:UniProtKB. DR GO; GO:0010506; P:regulation of autophagy; IEA:Ensembl. DR GO; GO:0000712; P:resolution of meiotic recombination intermediates; IBA:GO_Central. DR GO; GO:0009411; P:response to UV; IMP:UniProtKB. DR GO; GO:0000723; P:telomere maintenance; IMP:BHF-UCL. DR GO; GO:0061819; P:telomeric DNA-containing double minutes formation; IMP:BHF-UCL. DR GO; GO:0009650; P:UV protection; IEA:Ensembl. DR CDD; cd20078; XPF_nuclease_XPF_euk; 1. DR Gene3D; 3.40.50.10130; -; 1. DR Gene3D; 1.10.150.20; 5' to 3' exonuclease, C-terminal subdomain; 1. DR InterPro; IPR006166; ERCC4_domain. DR InterPro; IPR011335; Restrct_endonuc-II-like. DR InterPro; IPR010994; RuvA_2-like. DR InterPro; IPR006167; XPF. DR InterPro; IPR047520; XPF_nuclease. DR NCBIfam; TIGR00596; rad1; 1. DR PANTHER; PTHR10150; DNA REPAIR ENDONUCLEASE XPF; 1. DR PANTHER; PTHR10150:SF0; DNA REPAIR ENDONUCLEASE XPF; 1. DR Pfam; PF02732; ERCC4; 1. DR SMART; SM00891; ERCC4; 1. DR SUPFAM; SSF52980; Restriction endonuclease-like; 1. DR SUPFAM; SSF47781; RuvA domain 2-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Chromosome; KW Cockayne syndrome; Disease variant; DNA damage; DNA repair; DNA-binding; KW Dwarfism; Endonuclease; Fanconi anemia; Hydrolase; Isopeptide bond; KW Magnesium; Nuclease; Nucleus; Phosphoprotein; Reference proteome; Repeat; KW Ubl conjugation; Xeroderma pigmentosum. FT CHAIN 1..916 FT /note="DNA repair endonuclease XPF" FT /id="PRO_0000198853" FT DOMAIN 683..763 FT /note="ERCC4" FT REGION 1..457 FT /note="Helicase-like" FT /evidence="ECO:0000269|PubMed:16076955" FT REGION 233..254 FT /note="Leucine-zipper 1" FT /evidence="ECO:0000305|PubMed:8887684" FT REGION 270..298 FT /note="Leucine-zipper 2" FT /evidence="ECO:0000305|PubMed:8887684" FT REGION 460..487 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 502..526 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 658..813 FT /note="Nuclease" FT /evidence="ECO:0000269|PubMed:16076955" FT REGION 660..679 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 837..905 FT /note="HhH2, dimerization with ERCC1" FT /evidence="ECO:0000269|PubMed:16076955" FT MOTIF 486..491 FT /note="Nuclear localization signal" FT /evidence="ECO:0000255" FT COMPBIAS 511..526 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 289 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 521 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QZD4" FT MOD_RES 764 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QZD4" FT MOD_RES 911 FT /note="N6-acetyllysine" FT /evidence="ECO:0000269|PubMed:32034146" FT CROSSLNK 500 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 368..372 FT /note="ETKKE -> GILWG (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_056341" FT VAR_SEQ 373..916 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_056342" FT VARIANT 33 FT /note="V -> L (in dbSNP:rs34205098)" FT /id="VAR_057477" FT VARIANT 150 FT /note="R -> C (rare functional variant; causes mild FT disruption of interstrand cross-link repair activity; FT partial loss of protein stability; dbSNP:rs145402255)" FT /evidence="ECO:0000269|PubMed:24027083" FT /id="VAR_072084" FT VARIANT 153 FT /note="R -> P (in XFEPS; dbSNP:rs121913050)" FT /evidence="ECO:0000269|PubMed:17183314" FT /id="VAR_034802" FT VARIANT 168 FT /note="A -> V (in dbSNP:rs2020961)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_014769" FT VARIANT 225 FT /note="I -> M (in XP-F; dbSNP:rs764731249)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_008200" FT VARIANT 230 FT /note="L -> P (in FANCQ; dbSNP:rs397509402)" FT /evidence="ECO:0000269|PubMed:23623386" FT /id="VAR_070086" FT VARIANT 236 FT /note="C -> R (in XPF/CS; dbSNP:rs397509403)" FT /evidence="ECO:0000269|PubMed:23623389" FT /id="VAR_070087" FT VARIANT 267 FT /note="R -> H (in dbSNP:rs143479220)" FT /evidence="ECO:0000269|PubMed:24027083" FT /id="VAR_072085" FT VARIANT 379 FT /note="P -> S (in dbSNP:rs1799802)" FT /evidence="ECO:0000269|PubMed:9485007, ECO:0000269|Ref.2" FT /id="VAR_013395" FT VARIANT 415 FT /note="R -> Q (in dbSNP:rs1800067)" FT /evidence="ECO:0000269|PubMed:10479728, FT ECO:0000269|PubMed:14702039, ECO:0000269|Ref.2" FT /id="VAR_013396" FT VARIANT 454 FT /note="R -> W (in XP-F)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_008201" FT VARIANT 490 FT /note="R -> Q (in XP-F; dbSNP:rs912480692)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_008202" FT VARIANT 502 FT /note="E -> K (in XP-F)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_008203" FT VARIANT 513 FT /note="G -> R (in XP-F; dbSNP:rs769679311)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_008204" FT VARIANT 529 FT /note="I -> T (in XP-F)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_008205" FT VARIANT 567 FT /note="T -> A (in XP-F)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_008206" FT VARIANT 576 FT /note="R -> T (in dbSNP:rs1800068)" FT /evidence="ECO:0000269|PubMed:10479728" FT /id="VAR_013397" FT VARIANT 589 FT /note="R -> W (in XPF/CS; dbSNP:rs147105770)" FT /evidence="ECO:0000269|PubMed:23623389" FT /id="VAR_070088" FT VARIANT 605..611 FT /note="Missing (in XP-F)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_008207" FT VARIANT 608 FT /note="L -> P (in XP-F)" FT /evidence="ECO:0000269|PubMed:9580660" FT /id="VAR_013398" FT VARIANT 621 FT /note="T -> A (in dbSNP:rs2032331839)" FT /evidence="ECO:0000269|PubMed:24027083" FT /id="VAR_072086" FT VARIANT 662 FT /note="S -> P (in dbSNP:rs2020955)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_014770" FT VARIANT 689 FT /note="R -> S (in FANCQ; disruption of interstrand cross- FT link repair activity; no effect on protein stability; FT dbSNP:rs149364215)" FT /evidence="ECO:0000269|PubMed:23623386, FT ECO:0000269|PubMed:24027083" FT /id="VAR_070089" FT VARIANT 703 FT /note="G -> D" FT /evidence="ECO:0000269|PubMed:8797827" FT /id="VAR_005849" FT VARIANT 706 FT /note="I -> T (in dbSNP:rs1800069)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_014771" FT VARIANT 717 FT /note="I -> T" FT /evidence="ECO:0000269|PubMed:10479728" FT /id="VAR_013399" FT VARIANT 768 FT /note="S -> F (in dbSNP:rs12928650)" FT /id="VAR_057478" FT VARIANT 786 FT /note="S -> F (in FANCQ; disruption of interstrand cross- FT link repair activity; no effect on protein stability; FT dbSNP:rs1451008479)" FT /evidence="ECO:0000269|PubMed:24027083" FT /id="VAR_072087" FT VARIANT 799 FT /note="R -> W (in XP-F; mild; significant residual repair FT activity; dbSNP:rs121913049)" FT /evidence="ECO:0000269|PubMed:8797827, FT ECO:0000269|PubMed:9579555" FT /id="VAR_005850" FT VARIANT 860 FT /note="A -> D (in dbSNP:rs4986933)" FT /id="VAR_057479" FT VARIANT 873 FT /note="I -> V (in dbSNP:rs2020957)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_019201" FT VARIANT 875 FT /note="E -> G (in dbSNP:rs1800124)" FT /evidence="ECO:0000269|PubMed:10479728, ECO:0000269|Ref.2" FT /id="VAR_013408" FT VARIANT 912 FT /note="G -> E (in dbSNP:rs2020956)" FT /id="VAR_014772" FT MUTAGEN 911 FT /note="K->Q: Mimics acetylation; promoting interaction with FT ERCC1." FT /evidence="ECO:0000269|PubMed:32034146" FT MUTAGEN 911 FT /note="K->R: Abolished acetylation by KAT5, leading to FT decreased interaction with ERCC1." FT /evidence="ECO:0000269|PubMed:32034146" FT TURN 835..837 FT /evidence="ECO:0007829|PDB:2AQ0" FT HELIX 839..842 FT /evidence="ECO:0007829|PDB:1Z00" FT HELIX 850..853 FT /evidence="ECO:0007829|PDB:2A1J" FT HELIX 860..869 FT /evidence="ECO:0007829|PDB:2A1J" FT STRAND 870..872 FT /evidence="ECO:0007829|PDB:2KN7" FT HELIX 873..877 FT /evidence="ECO:0007829|PDB:2A1J" FT HELIX 881..888 FT /evidence="ECO:0007829|PDB:2A1J" FT HELIX 891..902 FT /evidence="ECO:0007829|PDB:2A1J" FT HELIX 905..908 FT /evidence="ECO:0007829|PDB:1Z00" FT STRAND 911..913 FT /evidence="ECO:0007829|PDB:1Z00" SQ SEQUENCE 916 AA; 104486 MW; C58CDE900378CCA8 CRC64; MESGQPARRI AMAPLLEYER QLVLELLDTD GLVVCARGLG ADRLLYHFLQ LHCHPACLVL VLNTQPAEEE YFINQLKIEG VEHLPRRVTN EITSNSRYEV YTQGGVIFAT SRILVVDFLT DRIPSDLITG ILVYRAHRII ESCQEAFILR LFRQKNKRGF IKAFTDNAVA FDTGFCHVER VMRNLFVRKL YLWPRFHVAV NSFLEQHKPE VVEIHVSMTP TMLAIQTAIL DILNACLKEL KCHNPSLEVE DLSLENAIGK PFDKTIRHYL DPLWHQLGAK TKSLVQDLKI LRTLLQYLSQ YDCVTFLNLL ESLRATEKAF GQNSGWLFLD SSTSMFINAR ARVYHLPDAK MSKKEKISEK MEIKEGEETK KELVLESNPK WEALTEVLKE IEAENKESEA LGGPGQVLIC ASDDRTCSQL RDYITLGAEA FLLRLYRKTF EKDSKAEEVW MKFRKEDSSK RIRKSHKRPK DPQNKERAST KERTLKKKKR KLTLTQMVGK PEELEEEGDV EEGYRREISS SPESCPEEIK HEEFDVNLSS DAAFGILKEP LTIIHPLLGC SDPYALTRVL HEVEPRYVVL YDAELTFVRQ LEIYRASRPG KPLRVYFLIY GGSTEEQRYL TALRKEKEAF EKLIREKASM VVPEEREGRD ETNLDLVRGT ASADVSTDTR KAGGQEQNGT QQSIVVDMRE FRSELPSLIH RRGIDIEPVT LEVGDYILTP EMCVERKSIS DLIGSLNNGR LYSQCISMSR YYKRPVLLIE FDPSKPFSLT SRGALFQEIS SNDISSKLTL LTLHFPRLRI LWCPSPHATA ELFEELKQSK PQPDAATALA ITADSETLPE SEKYNPGPQD FLLKMPGVNA KNCRSLMHHV KNIAELAALS QDELTSILGN AANAKQLYDF IHTSFAEVVS KGKGKK //