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Database: UniProt
Entry: O76064
LinkDB: O76064
Original site: O76064 
ID   RNF8_HUMAN              Reviewed;         485 AA.
AC   O76064; A6NN24; A8MYC0; B4DPG0; Q53H16; Q5NKW5;
DT   06-JUN-2002, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1998, sequence version 1.
DT   07-APR-2021, entry version 203.
DE   RecName: Full=E3 ubiquitin-protein ligase RNF8 {ECO:0000255|HAMAP-Rule:MF_03067};
DE            Short=hRNF8;
DE            EC=2.3.2.27 {ECO:0000255|HAMAP-Rule:MF_03067};
DE   AltName: Full=RING finger protein 8 {ECO:0000255|HAMAP-Rule:MF_03067};
DE   AltName: Full=RING-type E3 ubiquitin transferase RNF8 {ECO:0000255|HAMAP-Rule:MF_03067};
GN   Name=RNF8 {ECO:0000255|HAMAP-Rule:MF_03067}; Synonyms=KIAA0646;
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 / MRNA] (ISOFORM 1), AND TISSUE
RP   SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=9852682; DOI=10.1007/s100380050088;
RA   Seki N., Hattori A., Sugano S., Suzuki Y., Nakagawara A., Ohhira M.,
RA   Muramatsu M., Hori T., Saito T.;
RT   "Isolation, tissue expression, and chromosomal assignment of a novel human
RT   gene which encodes a protein with RING finger motif.";
RL   J. Hum. Genet. 43:272-274(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, TISSUE
RP   SPECIFICITY, INTERACTION WITH UBE2E2 AND UBE2N, AUTOUBIQUITINATION, AND
RP   MUTAGENESIS OF CYS-403.
RC   TISSUE=Fetal brain;
RX   PubMed=16215985; DOI=10.1002/jcb.20587;
RA   Plans V., Scheper J., Soler M., Loukili N., Okano Y., Thomson T.M.;
RT   "The RING finger protein RNF8 recruits UBC13 for lysine 63-based self
RT   polyubiquitylation.";
RL   J. Cell. Biochem. 97:572-582(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA   Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA   Nomura N., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. X. The
RT   complete sequences of 100 new cDNA clones from brain which can code for
RT   large proteins in vitro.";
RL   DNA Res. 5:169-176(1998).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Kidney;
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   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Hepatoma;
RA   Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA   Tanaka A., Yokoyama S.;
RL   Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=14574404; DOI=10.1038/nature02055;
RA   Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA   Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA   Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA   Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA   Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA   Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA   Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA   Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA   Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA   French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA   Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA   Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA   Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA   Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA   Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA   Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA   Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA   Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA   Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA   Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA   Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA   Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA   Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA   Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA   Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA   West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA   Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA   Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA   Rogers J., Beck S.;
RT   "The DNA sequence and analysis of human chromosome 6.";
RL   Nature 425:805-811(2003).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Muscle;
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   [10]
RP   PROTEIN SEQUENCE OF 81-89; 156-173 AND 215-226, FUNCTION, SUBCELLULAR
RP   LOCATION, MASS SPECTROMETRY, AND MUTAGENESIS OF ARG-42.
RX   PubMed=23233665; DOI=10.1074/jbc.m112.423392;
RA   Zhang S., Zhou Y., Sarkeshik A., Yates J.R. III, Thomson T.M., Zhang Z.,
RA   Lee E.Y., Lee M.Y.;
RT   "Identification of RNF8 as a ubiquitin ligase involved in targeting the p12
RT   subunit of DNA polymerase delta for degradation in response to DNA
RT   damage.";
RL   J. Biol. Chem. 288:2941-2950(2013).
RN   [11]
RP   FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH UBE2E1; UBE2E2 AND UBE2E3,
RP   AND MUTAGENESIS OF CYS-403.
RX   PubMed=11322894; DOI=10.1046/j.1432-1327.2001.02169.x;
RA   Ito K., Adachi S., Iwakami R., Yasuda H., Muto Y., Seki N., Okano Y.;
RT   "N-terminally extended human ubiquitin-conjugating enzymes (E2s) mediate
RT   the ubiquitination of RING-finger proteins, ARA54 and RNF8.";
RL   Eur. J. Biochem. 268:2725-2732(2001).
RN   [12]
RP   FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RXRA, AND MUTAGENESIS OF
RP   CYS-403.
RX   PubMed=14981089; DOI=10.1074/jbc.m309148200;
RA   Takano Y., Adachi S., Okuno M., Muto Y., Yoshioka T.,
RA   Matsushima-Nishiwaki R., Tsurumi H., Ito K., Friedman S.L., Moriwaki H.,
RA   Kojima S., Okano Y.;
RT   "The RING finger protein, RNF8, interacts with retinoid X receptor alpha
RT   and enhances its transcription-stimulating activity.";
RL   J. Biol. Chem. 279:18926-18934(2004).
RN   [13]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH MDC1,
RP   DOMAIN, AND MUTAGENESIS OF ARG-42 AND CYS-403.
RX   PubMed=18001824; DOI=10.1016/j.cell.2007.09.040;
RA   Mailand N., Bekker-Jensen S., Faustrup H., Melander F., Bartek J.,
RA   Lukas C., Lukas J.;
RT   "RNF8 ubiquitylates histones at DNA double-strand breaks and promotes
RT   assembly of repair proteins.";
RL   Cell 131:887-900(2007).
RN   [14]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=18077395; DOI=10.1073/pnas.0710061104;
RA   Wang B., Elledge S.J.;
RT   "Ubc13/Rnf8 ubiquitin ligases control foci formation of the
RT   Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:20759-20763(2007).
RN   [15]
RP   FUNCTION, AND INTERACTION WITH MDC1.
RX   PubMed=18006705; DOI=10.1126/science.1150034;
RA   Kolas N.K., Chapman J.R., Nakada S., Ylanko J., Chahwan R., Sweeney F.D.,
RA   Panier S., Mendez M., Wildenhain J., Thomson T.M., Pelletier L.,
RA   Jackson S.P., Durocher D.;
RT   "Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase.";
RL   Science 318:1637-1640(2007).
RN   [16]
RP   FUNCTION, AND DEVELOPMENTAL STAGE.
RX   PubMed=17724460; DOI=10.1038/sj.onc.1210782;
RA   Plans V., Guerra-Rebollo M., Thomson T.M.;
RT   "Regulation of mitotic exit by the RNF8 ubiquitin ligase.";
RL   Oncogene 27:1355-1365(2008).
RN   [17]
RP   FUNCTION.
RX   PubMed=18948756; DOI=10.4161/cc.7.21.6949;
RA   Zhang S., Chea J., Meng X., Zhou Y., Lee E.Y.C., Lee M.Y.W.T.;
RT   "PCNA is ubiquitinated by RNF8.";
RL   Cell Cycle 7:3399-3404(2008).
RN   [18]
RP   FUNCTION.
RX   PubMed=18337245; DOI=10.1074/jbc.m710197200;
RA   Sakasai R., Tibbetts R.;
RT   "RNF8-dependent and RNF8-independent regulation of 53BP1 in response to DNA
RT   damage.";
RL   J. Biol. Chem. 283:13549-13555(2008).
RN   [19]
RP   INTERACTION WITH UBE2N.
RX   PubMed=18678647; DOI=10.1128/mcb.00987-08;
RA   Huen M.S.Y., Huang J., Yuan J., Yamamoto M., Akira S., Ashley C., Xiao W.,
RA   Chen J.;
RT   "Noncanonical E2 variant-independent function of UBC13 in promoting
RT   checkpoint protein assembly.";
RL   Mol. Cell. Biol. 28:6104-6112(2008).
RN   [20]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-157, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [21]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-157, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [22]
RP   INTERACTION WITH HERC2.
RX   PubMed=20023648; DOI=10.1038/ncb2008;
RA   Bekker-Jensen S., Rendtlew Danielsen J., Fugger K., Gromova I.,
RA   Nerstedt A., Lukas C., Bartek J., Lukas J., Mailand N.;
RT   "HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on
RT   damaged chromosomes.";
RL   Nat. Cell Biol. 12:80-86(2010).
RN   [23]
RP   FUNCTION.
RX   PubMed=19203578; DOI=10.1016/j.cell.2008.12.042;
RA   Stewart G.S., Panier S., Townsend K., Al-Hakim A.K., Kolas N.K.,
RA   Miller E.S., Nakada S., Ylanko J., Olivarius S., Mendez M., Oldreive C.,
RA   Wildenhain J., Tagliaferro A., Pelletier L., Taubenheim N., Durandy A.,
RA   Byrd P.J., Stankovic T., Taylor A.M.R., Durocher D.;
RT   "The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling
RT   cascade at sites of DNA damage.";
RL   Cell 136:420-434(2009).
RN   [24]
RP   FUNCTION.
RX   PubMed=19203579; DOI=10.1016/j.cell.2008.12.041;
RA   Doil C., Mailand N., Bekker-Jensen S., Menard P., Larsen D.H.,
RA   Pepperkok R., Ellenberg J., Panier S., Durocher D., Bartek J., Lukas J.,
RA   Lukas C.;
RT   "RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to
RT   allow accumulation of repair proteins.";
RL   Cell 136:435-446(2009).
RN   [25]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=19124460; DOI=10.1074/jbc.m809158200;
RA   Gong Z., Cho Y.-W., Kim J.-E., Ge K., Chen J.;
RT   "Accumulation of Pax2 transactivation domain interaction protein (PTIP) at
RT   sites of DNA breaks via RNF8-dependent pathway is required for cell
RT   survival after DNA damage.";
RL   J. Biol. Chem. 284:7284-7293(2009).
RN   [26]
RP   FUNCTION.
RX   PubMed=19015238; DOI=10.1128/mcb.01302-08;
RA   Wu J., Huen M.S.Y., Lu L.-Y., Ye L., Dou Y., Ljungman M., Chen J., Yu X.;
RT   "Histone ubiquitination associates with BRCA1-dependent DNA damage
RT   response.";
RL   Mol. Cell. Biol. 29:849-860(2009).
RN   [27]
RP   FUNCTION.
RX   PubMed=19202061; DOI=10.1073/pnas.0807485106;
RA   Shao G., Lilli D.R., Patterson-Fortin J., Coleman K.A., Morrissey D.E.,
RA   Greenberg R.A.;
RT   "The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-
RT   dependent ubiquitination events at DNA double strand breaks.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:3166-3171(2009).
RN   [28]
RP   FUNCTION.
RX   PubMed=20550933; DOI=10.1016/j.cell.2010.04.038;
RA   Shanbhag N.M., Rafalska-Metcalf I.U., Balane-Bolivar C., Janicki S.M.,
RA   Greenberg R.A.;
RT   "ATM-dependent chromatin changes silence transcription in cis to DNA
RT   double-strand breaks.";
RL   Cell 141:970-981(2010).
RN   [29]
RP   FUNCTION.
RX   PubMed=21558560; DOI=10.1074/jbc.m111.232041;
RA   Sy S.M., Jiang J., Dong S.S., Lok G.T., Wu J., Cai H., Yeung E.S.,
RA   Huang J., Chen J., Deng Y., Huen M.S.;
RT   "Critical roles of ring finger protein RNF8 in replication stress
RT   responses.";
RL   J. Biol. Chem. 286:22355-22361(2011).
RN   [30]
RP   FUNCTION, AND MUTAGENESIS OF ARG-42 AND CYS-406.
RX   PubMed=21857671; DOI=10.1038/ncb2326;
RA   Peuscher M.H., Jacobs J.J.;
RT   "DNA-damage response and repair activities at uncapped telomeres depend on
RT   RNF8.";
RL   Nat. Cell Biol. 13:1139-1145(2011).
RN   [31]
RP   FUNCTION.
RX   PubMed=22865450; DOI=10.1158/0008-5472.can-12-1057;
RA   Nakada S., Yonamine R.M., Matsuo K.;
RT   "RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the
RT   absence of BRCA1 and 53BP1.";
RL   Cancer Res. 72:4974-4983(2012).
RN   [32]
RP   FUNCTION IN UBIQUITINATION OF KDM4A, AND MUTAGENESIS OF ILE-405.
RX   PubMed=22373579; DOI=10.1038/emboj.2012.47;
RA   Mallette F.A., Mattiroli F., Cui G., Young L.C., Hendzel M.J., Mer G.,
RA   Sixma T.K., Richard S.;
RT   "RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1
RT   recruitment to DNA damage sites.";
RL   EMBO J. 31:1865-1878(2012).
RN   [33]
RP   FUNCTION.
RX   PubMed=22531782; DOI=10.1038/emboj.2012.104;
RA   Luijsterburg M.S., Acs K., Ackermann L., Wiegant W.W., Bekker-Jensen S.,
RA   Larsen D.H., Khanna K.K., van Attikum H., Mailand N., Dantuma N.P.;
RT   "A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-
RT   order chromatin structure.";
RL   EMBO J. 31:2511-2527(2012).
RN   [34]
RP   INTERACTION WITH HUMAN HERPESVIRUS 1 ICP0 (MICROBIAL INFECTION), AND
RP   MUTAGENESIS OF ARG-42.
RX   PubMed=22405594; DOI=10.1016/j.molcel.2012.02.004;
RA   Chaurushiya M.S., Lilley C.E., Aslanian A., Meisenhelder J., Scott D.C.,
RA   Landry S., Ticau S., Boutell C., Yates J.R. III, Schulman B.A., Hunter T.,
RA   Weitzman M.D.;
RT   "Viral E3 ubiquitin ligase-mediated degradation of a cellular E3: viral
RT   mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain.";
RL   Mol. Cell 46:79-90(2012).
RN   [35]
RP   FUNCTION.
RX   PubMed=22705371; DOI=10.1016/j.molcel.2012.05.026;
RA   Yan Z., Guo R., Paramasivam M., Shen W., Ling C., Fox D. III, Wang Y.,
RA   Oostra A.B., Kuehl J., Lee D.Y., Takata M., Hoatlin M.E., Schindler D.,
RA   Joenje H., de Winter J.P., Li L., Seidman M.M., Wang W.;
RT   "A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to
RT   the Fanconi anemia DNA repair network.";
RL   Mol. Cell 47:61-75(2012).
RN   [36]
RP   FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH UBE2N.
RX   PubMed=22266820; DOI=10.1038/nsmb.2211;
RA   Feng L., Chen J.;
RT   "The E3 ligase RNF8 regulates KU80 removal and NHEJ repair.";
RL   Nat. Struct. Mol. Biol. 19:201-206(2012).
RN   [37]
RP   FUNCTION, AND MUTAGENESIS OF ILE-405.
RX   PubMed=21911360; DOI=10.1093/nar/gkr655;
RA   Lok G.T., Sy S.M., Dong S.S., Ching Y.P., Tsao S.W., Thomson T.M.,
RA   Huen M.S.;
RT   "Differential regulation of RNF8-mediated Lys48- and Lys63-based poly-
RT   ubiquitylation.";
RL   Nucleic Acids Res. 40:196-205(2012).
RN   [38]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-157, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [39]
RP   INTERACTION WITH WRAP53.
RX   PubMed=25512560; DOI=10.1101/gad.246546.114;
RA   Henriksson S., Rassoolzadeh H., Hedstroem E., Coucoravas C., Julner A.,
RA   Goldstein M., Imreh G., Zhivotovsky B., Kastan M.B., Helleday T.,
RA   Farnebo M.;
RT   "The scaffold protein WRAP53beta orchestrates the ubiquitin response
RT   critical for DNA double-strand break repair.";
RL   Genes Dev. 28:2726-2738(2014).
RN   [40]
RP   STRUCTURE BY NMR OF 8-139.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of the FHA domain of human ubiquitin ligase protein
RT   RNF8.";
RL   Submitted (NOV-2005) to the PDB data bank.
RN   [41]
RP   X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) OF 13-146 IN COMPLEX WITH
RP   PHOSPHOPEPTIDE, FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=18001825; DOI=10.1016/j.cell.2007.09.041;
RA   Huen M.S.Y., Grant R., Manke I., Minn K., Yu X., Yaffe M.B., Chen J.;
RT   "RNF8 transduces the DNA-damage signal via histone ubiquitylation and
RT   checkpoint protein assembly.";
RL   Cell 131:901-914(2007).
RN   [42]
RP   X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 351-483 IN COMPLEX WITH ZINC,
RP   SUBUNIT, FUNCTION, AND MUTAGENESIS OF ASP-443.
RX   PubMed=22980979; DOI=10.1016/j.cell.2012.08.005;
RA   Mattiroli F., Vissers J.H., van Dijk W.J., Ikpa P., Citterio E.,
RA   Vermeulen W., Marteijn J.A., Sixma T.K.;
RT   "RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA Damage signaling.";
RL   Cell 150:1182-1195(2012).
RN   [43]
RP   X-RAY CRYSTALLOGRAPHY (4.8 ANGSTROMS) OF 345-485 IN COMPLEX WITH UBE2N, AND
RP   MUTAGENESIS OF ILE-405.
RX   PubMed=22589545; DOI=10.1074/jbc.m112.359653;
RA   Campbell S.J., Edwards R.A., Leung C.C., Neculai D., Hodge C.D.,
RA   Dhe-Paganon S., Glover J.N.;
RT   "Molecular insights into the function of RING Finger (RNF)-containing
RT   proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent ubiquitylation.";
RL   J. Biol. Chem. 287:23900-23910(2012).
CC   -!- FUNCTION: E3 ubiquitin-protein ligase that plays a key role in DNA
CC       damage signaling via 2 distinct roles: by mediating the 'Lys-63'-linked
CC       ubiquitination of histones H2A and H2AX and promoting the recruitment
CC       of DNA repair proteins at double-strand breaks (DSBs) sites, and by
CC       catalyzing 'Lys-48'-linked ubiquitination to remove target proteins
CC       from DNA damage sites. Following DNA DSBs, it is recruited to the sites
CC       of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked
CC       ubiquitination of histones H2A and H2AX, thereby promoting the
CC       formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF).
CC       Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and
CC       PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand
CC       cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination
CC       of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and
CC       Fanconi anemia (FA) complex, followed by interstrand cross-link repair.
CC       H2A ubiquitination also mediates the ATM-dependent transcriptional
CC       silencing at regions flanking DSBs in cis, a mechanism to avoid
CC       collision between transcription and repair intermediates. Promotes the
CC       formation of 'Lys-63'-linked polyubiquitin chains via interactions with
CC       the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-
CC       histone substrates such as PCNA. Substrates that are polyubiquitinated
CC       at 'Lys-63' are usually not targeted for degradation. Also catalyzes
CC       the formation of 'Lys-48'-linked polyubiquitin chains via interaction
CC       with the ubiquitin-conjugating UBE2L6/UBCH8, leading to degradation of
CC       substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is
CC       still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-
CC       linked ubiquitination is regulated but it could be due to RNF8 ability
CC       to interact with specific E2 specific ligases. For instance,
CC       interaction with phosphorylated HERC2 promotes the association between
CC       RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-
CC       linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by
CC       promoting the 'Lys-48'-linked ubiquitination and degradation the of
CC       KU80/XRCC5. Following DNA damage, mediates the ubiquitination and
CC       degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to
CC       unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA
CC       damage sites (PubMed:11322894, PubMed:14981089, PubMed:17724460,
CC       PubMed:18001824, PubMed:18001825, PubMed:18006705, PubMed:18077395,
CC       PubMed:18337245, PubMed:18948756, PubMed:19015238, PubMed:19124460,
CC       PubMed:19202061, PubMed:19203578, PubMed:19203579, PubMed:20550933,
CC       PubMed:21558560, PubMed:21857671, PubMed:21911360, PubMed:22266820,
CC       PubMed:22373579, PubMed:22531782, PubMed:22705371, PubMed:22865450,
CC       PubMed:22980979). Following DNA damage, mediates the ubiquitination and
CC       degradation of POLD4/p12, a subunit of DNA polymerase delta. In the
CC       absence of POLD4, DNA polymerase delta complex exhibits higher
CC       proofreading activity (PubMed:23233665). In addition to its function in
CC       damage signaling, also plays a role in higher-order chromatin structure
CC       by mediating extensive chromatin decondensation. Involved in the
CC       activation of ATM by promoting histone H2B ubiquitination, which
CC       indirectly triggers histone H4 'Lys-16' acetylation (H4K16ac),
CC       establishing a chromatin environment that promotes efficient activation
CC       of ATM kinase. Required in the testis, where it plays a role in the
CC       replacement of histones during spermatogenesis. At uncapped telomeres,
CC       promotes the joining of deprotected chromosome ends by inducing H2A
CC       ubiquitination and TP53BP1 recruitment, suggesting that it may enhance
CC       cancer development by aggravating telomere-induced genome instability
CC       in case of telomeric crisis. Promotes the assembly of RAD51 at DNA DSBs
CC       in the absence of BRCA1 and TP53BP1 Also involved in class switch
CC       recombination in immune system, via its role in regulation of DSBs
CC       repair. May be required for proper exit from mitosis after spindle
CC       checkpoint activation and may regulate cytokinesis. May play a role in
CC       the regulation of RXRA-mediated transcriptional activity. Not involved
CC       in RXRA ubiquitination by UBE2E2 (PubMed:11322894, PubMed:14981089,
CC       PubMed:17724460, PubMed:18001824, PubMed:18001825, PubMed:18006705,
CC       PubMed:18077395, PubMed:18337245, PubMed:18948756, PubMed:19015238,
CC       PubMed:19124460, PubMed:19202061, PubMed:19203578, PubMed:19203579,
CC       PubMed:20550933, PubMed:21558560, PubMed:21857671, PubMed:21911360,
CC       PubMed:22266820, PubMed:22373579, PubMed:22531782, PubMed:22705371,
CC       PubMed:22865450, PubMed:22980979). {ECO:0000269|PubMed:11322894,
CC       ECO:0000269|PubMed:14981089, ECO:0000269|PubMed:17724460,
CC       ECO:0000269|PubMed:18001824, ECO:0000269|PubMed:18001825,
CC       ECO:0000269|PubMed:18006705, ECO:0000269|PubMed:18077395,
CC       ECO:0000269|PubMed:18337245, ECO:0000269|PubMed:18948756,
CC       ECO:0000269|PubMed:19015238, ECO:0000269|PubMed:19124460,
CC       ECO:0000269|PubMed:19202061, ECO:0000269|PubMed:19203578,
CC       ECO:0000269|PubMed:19203579, ECO:0000269|PubMed:20550933,
CC       ECO:0000269|PubMed:21558560, ECO:0000269|PubMed:21857671,
CC       ECO:0000269|PubMed:21911360, ECO:0000269|PubMed:22266820,
CC       ECO:0000269|PubMed:22373579, ECO:0000269|PubMed:22531782,
CC       ECO:0000269|PubMed:22705371, ECO:0000269|PubMed:22865450,
CC       ECO:0000269|PubMed:22980979, ECO:0000269|PubMed:23233665}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC         [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC         cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC         EC=2.3.2.27; Evidence={ECO:0000255|HAMAP-Rule:MF_03067};
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC       {ECO:0000255|HAMAP-Rule:MF_03067}.
CC   -!- SUBUNIT: Homodimer. Forms a E2-E3 ubiquitin ligase complex composed of
CC       the RNF8 homodimer and a E2 heterodimer of UBE2N and UBE2V2. Interacts
CC       with class III E2s, including UBE2E1, UBE2E2, and UBE2E3 and with
CC       UBE2N. Interacts with RXRA. Interacts (via FHA domain) with ATM-
CC       phosphorylated MDC1. Interacts (via FHA domain) with 'Thr-4827'
CC       phosphorylated HERC2 (via C-terminus). Interacts with PIWIL1; leading
CC       to sequester RNF8 in the cytoplasm (By similarity). Interacts with
CC       WRAP53/TCAB1 (PubMed:25512560). {ECO:0000250|UniProtKB:Q8VC56,
CC       ECO:0000269|PubMed:11322894, ECO:0000269|PubMed:14981089,
CC       ECO:0000269|PubMed:16215985, ECO:0000269|PubMed:18001824,
CC       ECO:0000269|PubMed:18001825, ECO:0000269|PubMed:18006705,
CC       ECO:0000269|PubMed:18678647, ECO:0000269|PubMed:20023648,
CC       ECO:0000269|PubMed:22266820, ECO:0000269|PubMed:22589545,
CC       ECO:0000269|PubMed:22980979, ECO:0000269|PubMed:25512560}.
CC   -!- SUBUNIT: (Microbial infection) Interacts (via FHA domain) with
CC       phosphorylated human herpesvirus 1 ICP0 protein; leading to RNF8
CC       degradation by the proteasome. {ECO:0000269|PubMed:22405594}.
CC   -!- INTERACTION:
CC       O76064; Q9Y2J4: AMOTL2; NbExp=3; IntAct=EBI-373337, EBI-746752;
CC       O76064; Q53TS8: C2CD6; NbExp=3; IntAct=EBI-373337, EBI-739879;
CC       O76064; Q9P1Z2: CALCOCO1; NbExp=3; IntAct=EBI-373337, EBI-749920;
CC       O76064; Q49A88-3: CCDC14; NbExp=3; IntAct=EBI-373337, EBI-12105646;
CC       O76064; Q8IVM0: CCDC50; NbExp=3; IntAct=EBI-373337, EBI-723996;
CC       O76064; Q9C0F1: CEP44; NbExp=4; IntAct=EBI-373337, EBI-744115;
CC       O76064; Q6P2H3-3: CEP85; NbExp=3; IntAct=EBI-373337, EBI-12368239;
CC       O76064; P49760: CLK2; NbExp=5; IntAct=EBI-373337, EBI-750020;
CC       O76064; P49761: CLK3; NbExp=3; IntAct=EBI-373337, EBI-745579;
CC       O76064; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-373337, EBI-742054;
CC       O76064; P50570: DNM2; NbExp=3; IntAct=EBI-373337, EBI-346547;
CC       O76064; Q5QJE6: DNTTIP2; NbExp=3; IntAct=EBI-373337, EBI-5666736;
CC       O76064; O95208-2: EPN2; NbExp=3; IntAct=EBI-373337, EBI-12135243;
CC       O76064; I6L9I8: EPN3; NbExp=3; IntAct=EBI-373337, EBI-12866582;
CC       O76064; Q9BPY3: FAM118B; NbExp=3; IntAct=EBI-373337, EBI-726822;
CC       O76064; Q8IZU0: FAM9B; NbExp=3; IntAct=EBI-373337, EBI-10175124;
CC       O76064; A1L4K1: FSD2; NbExp=3; IntAct=EBI-373337, EBI-5661036;
CC       O76064; Q96D09: GPRASP2; NbExp=3; IntAct=EBI-373337, EBI-473189;
CC       O76064; V9HW80: HEL-S-70; NbExp=3; IntAct=EBI-373337, EBI-10175326;
CC       O76064; Q8IX15-3: HOMEZ; NbExp=3; IntAct=EBI-373337, EBI-10172004;
CC       O76064; Q63ZY3: KANK2; NbExp=3; IntAct=EBI-373337, EBI-2556193;
CC       O76064; Q5T7B8-2: KIF24; NbExp=3; IntAct=EBI-373337, EBI-10213781;
CC       O76064; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-373337, EBI-10171774;
CC       O76064; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-373337, EBI-1044640;
CC       O76064; Q9BYQ0: KRTAP9-8; NbExp=3; IntAct=EBI-373337, EBI-11958364;
CC       O76064; P61968: LMO4; NbExp=3; IntAct=EBI-373337, EBI-2798728;
CC       O76064; Q9Y6D9: MAD1L1; NbExp=7; IntAct=EBI-373337, EBI-742610;
CC       O76064; P28482: MAPK1; NbExp=3; IntAct=EBI-373337, EBI-959949;
CC       O76064; Q14676: MDC1; NbExp=11; IntAct=EBI-373337, EBI-495644;
CC       O76064; P49585: PCYT1A; NbExp=3; IntAct=EBI-373337, EBI-2563309;
CC       O76064; O15173: PGRMC2; NbExp=3; IntAct=EBI-373337, EBI-1050125;
CC       O76064; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-373337, EBI-79165;
CC       O76064; Q9UL42: PNMA2; NbExp=7; IntAct=EBI-373337, EBI-302355;
CC       O76064; Q96CD2: PPCDC; NbExp=3; IntAct=EBI-373337, EBI-724333;
CC       O76064; P20618: PSMB1; NbExp=3; IntAct=EBI-373337, EBI-372273;
CC       O76064; O43251: RBFOX2; NbExp=3; IntAct=EBI-373337, EBI-746056;
CC       O76064; O43251-10: RBFOX2; NbExp=3; IntAct=EBI-373337, EBI-11963050;
CC       O76064; O76064: RNF8; NbExp=6; IntAct=EBI-373337, EBI-373337;
CC       O76064; Q9NY72: SCN3B; NbExp=3; IntAct=EBI-373337, EBI-17247926;
CC       O76064; Q9UH03: SEPTIN3; NbExp=7; IntAct=EBI-373337, EBI-727037;
CC       O76064; Q8IVP1: SH3GL3; NbExp=3; IntAct=EBI-373337, EBI-6503765;
CC       O76064; O75558: STX11; NbExp=6; IntAct=EBI-373337, EBI-714135;
CC       O76064; Q9BSE2: TMEM79; NbExp=10; IntAct=EBI-373337, EBI-8649725;
CC       O76064; Q15025: TNIP1; NbExp=3; IntAct=EBI-373337, EBI-357849;
CC       O76064; Q6UXN7: TOMM20L; NbExp=3; IntAct=EBI-373337, EBI-11954062;
CC       O76064; P62837: UBE2D2; NbExp=4; IntAct=EBI-373337, EBI-347677;
CC       O76064; Q99986: VRK1; NbExp=2; IntAct=EBI-373337, EBI-1769146;
CC       O76064; Q9Y3C0: WASHC3; NbExp=3; IntAct=EBI-373337, EBI-712969;
CC       O76064; O00401: WASL; NbExp=8; IntAct=EBI-373337, EBI-957615;
CC       O76064; Q96DT7-3: ZBTB10; NbExp=3; IntAct=EBI-373337, EBI-12017160;
CC       O76064; Q9UL40: ZNF346; NbExp=3; IntAct=EBI-373337, EBI-2462313;
CC       O76064; Q96IT1: ZNF496; NbExp=3; IntAct=EBI-373337, EBI-743906;
CC       O76064-1; Q14676: MDC1; NbExp=2; IntAct=EBI-15964690, EBI-495644;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|HAMAP-Rule:MF_03067,
CC       ECO:0000269|PubMed:11322894, ECO:0000269|PubMed:14981089,
CC       ECO:0000269|PubMed:16215985, ECO:0000269|PubMed:23233665}. Cytoplasm
CC       {ECO:0000255|HAMAP-Rule:MF_03067}. Midbody {ECO:0000255|HAMAP-
CC       Rule:MF_03067}. Chromosome, telomere {ECO:0000255|HAMAP-Rule:MF_03067}.
CC       Note=Recruited at uncapped telomeres (By similarity). Following DNA
CC       damage, such as double-strand breaks, recruited to the sites of damage
CC       (PubMed:18001824, PubMed:18077395, PubMed:22266820, PubMed:23233665).
CC       During prophase, concomitant with nuclear envelope breakdown, localizes
CC       throughout the cell, with a dotted pattern. In telophase, again in the
CC       nucleus and also with a discrete dotted pattern in the cytoplasm. In
CC       late telophase and during cytokinesis, localizes in the midbody of the
CC       tubulin bridge joining the daughter cells. Does not seem to be
CC       associated with condensed chromosomes at any time during the cell
CC       cycle. During spermatogenesis, sequestered in the cytoplasm by PIWIL1:
CC       RNF8 is released following ubiquitination and degradation of PIWIL1.
CC       {ECO:0000255|HAMAP-Rule:MF_03067, ECO:0000269|PubMed:18001824,
CC       ECO:0000269|PubMed:18077395, ECO:0000269|PubMed:22266820,
CC       ECO:0000269|PubMed:23233665}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=O76064-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O76064-2; Sequence=VSP_036671, VSP_037831;
CC       Name=3;
CC         IsoId=O76064-3; Sequence=VSP_054037, VSP_054038;
CC   -!- TISSUE SPECIFICITY: Ubiquitous. In fetal tissues, highest expression in
CC       brain, thymus and liver. In adult tissues, highest levels in brain and
CC       testis, lowest levels in peripheral blood cells.
CC       {ECO:0000269|PubMed:16215985, ECO:0000269|PubMed:9852682}.
CC   -!- DEVELOPMENTAL STAGE: Low levels at the G1-S boundary increase in
CC       intensity during S phase and until the end of the G2 phase. Abruptly
CC       decreases in late mitosis (at protein level). Barely detectable in
CC       anaphase. {ECO:0000269|PubMed:17724460}.
CC   -!- DOMAIN: The FHA domain specifically recognizes and binds ATM-
CC       phosphorylated MDC1 and 'Thr-4827' phosphorylated HERC2
CC       (PubMed:18001824). This domain is required for proper recruitment to
CC       DNA damage sites after UV irradiation, ionizing radiation, or treatment
CC       with an alkylating agent (PubMed:23233665).
CC       {ECO:0000269|PubMed:18001824, ECO:0000269|PubMed:23233665}.
CC   -!- PTM: Autoubiquitinated through 'Lys-48' and 'Lys-63' of ubiquitin.
CC       'Lys-63' polyubiquitination is mediated by UBE2N. 'Lys-29'-type
CC       polyubiquitination is also observed, but it doesn't require its own
CC       functional RING-type zinc finger. {ECO:0000255|HAMAP-Rule:MF_03067,
CC       ECO:0000269|PubMed:16215985}.
CC   -!- MISCELLANEOUS: [Isoform 2]: May be produced at very low levels due to a
CC       premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC       decay. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the RNF8 family. {ECO:0000255|HAMAP-
CC       Rule:MF_03067}.
CC   -!- CAUTION: According to a well-established model, RNF8 initiate H2A 'Lys-
CC       63'-linked ubiquitination leading to recruitment of RNF168 to amplify
CC       H2A 'Lys-63'-linked ubiquitination (PubMed:19203578 and
CC       PubMed:19203579). However, other data suggest that RNF168 is the
CC       priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13'
CC       and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub
CC       respectively) (PubMed:22980979). These data suggest that RNF168 might
CC       be recruited to DSBs sites in a RNF8-dependent manner by binding to
CC       non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates
CC       monoubiquitination of H2A, which is then amplified by RNF8
CC       (PubMed:22980979). Additional evidence is however required to confirm
CC       these data. {ECO:0000255|HAMAP-Rule:MF_03067,
CC       ECO:0000305|PubMed:22980979}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA31621.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=BAG60572.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305};
CC       Sequence=EAX03945.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR   EMBL; AB012770; BAA33557.1; -; Genomic_DNA.
DR   EMBL; AF334675; AAQ14887.1; -; mRNA.
DR   EMBL; AB014546; BAA31621.2; ALT_INIT; mRNA.
DR   EMBL; AK298319; BAG60572.1; ALT_SEQ; mRNA.
DR   EMBL; BT007446; AAP36114.1; -; mRNA.
DR   EMBL; AK222765; BAD96485.1; -; mRNA.
DR   EMBL; AL096712; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471081; EAX03944.1; -; Genomic_DNA.
DR   EMBL; CH471081; EAX03945.1; ALT_SEQ; Genomic_DNA.
DR   EMBL; BC007517; AAH07517.1; -; mRNA.
DR   CCDS; CCDS4833.1; -. [O76064-3]
DR   CCDS; CCDS4834.1; -. [O76064-1]
DR   RefSeq; NP_003949.1; NM_003958.3. [O76064-1]
DR   RefSeq; NP_898901.1; NM_183078.2. [O76064-3]
DR   PDB; 2CSW; NMR; -; A=8-139.
DR   PDB; 2PIE; X-ray; 1.35 A; A=13-146.
DR   PDB; 4AYC; X-ray; 1.90 A; A/B=351-485.
DR   PDB; 4ORH; X-ray; 4.80 A; C/G/H/K/L=345-485.
DR   PDB; 4WHV; X-ray; 8.30 A; C/D/I/J=345-485.
DR   PDBsum; 2CSW; -.
DR   PDBsum; 2PIE; -.
DR   PDBsum; 4AYC; -.
DR   PDBsum; 4ORH; -.
DR   PDBsum; 4WHV; -.
DR   BMRB; O76064; -.
DR   SASBDB; O76064; -.
DR   SMR; O76064; -.
DR   BioGRID; 114492; 110.
DR   CORUM; O76064; -.
DR   DIP; DIP-31265N; -.
DR   IntAct; O76064; 78.
DR   MINT; O76064; -.
DR   STRING; 9606.ENSP00000362578; -.
DR   iPTMnet; O76064; -.
DR   PhosphoSitePlus; O76064; -.
DR   BioMuta; RNF8; -.
DR   EPD; O76064; -.
DR   jPOST; O76064; -.
DR   MassIVE; O76064; -.
DR   MaxQB; O76064; -.
DR   PaxDb; O76064; -.
DR   PeptideAtlas; O76064; -.
DR   PRIDE; O76064; -.
DR   ProteomicsDB; 50370; -. [O76064-1]
DR   ProteomicsDB; 50371; -. [O76064-2]
DR   Antibodypedia; 15585; 328 antibodies.
DR   DNASU; 9025; -.
DR   Ensembl; ENST00000229866; ENSP00000229866; ENSG00000112130. [O76064-2]
DR   Ensembl; ENST00000373479; ENSP00000362578; ENSG00000112130. [O76064-1]
DR   Ensembl; ENST00000469731; ENSP00000418879; ENSG00000112130. [O76064-3]
DR   GeneID; 9025; -.
DR   KEGG; hsa:9025; -.
DR   UCSC; uc003onq.4; human. [O76064-1]
DR   CTD; 9025; -.
DR   DisGeNET; 9025; -.
DR   GeneCards; RNF8; -.
DR   HGNC; HGNC:10071; RNF8.
DR   HPA; ENSG00000112130; Low tissue specificity.
DR   MIM; 611685; gene.
DR   neXtProt; NX_O76064; -.
DR   OpenTargets; ENSG00000112130; -.
DR   PharmGKB; PA34445; -.
DR   VEuPathDB; HostDB:ENSG00000112130.16; -.
DR   eggNOG; KOG3872; Eukaryota.
DR   GeneTree; ENSGT00400000022349; -.
DR   HOGENOM; CLU_023453_1_0_1; -.
DR   InParanoid; O76064; -.
DR   OMA; SYCISEW; -.
DR   OrthoDB; 1585372at2759; -.
DR   PhylomeDB; O76064; -.
DR   TreeFam; TF330957; -.
DR   PathwayCommons; O76064; -.
DR   Reactome; R-HSA-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR   Reactome; R-HSA-5693571; Nonhomologous End-Joining (NHEJ).
DR   Reactome; R-HSA-5693607; Processing of DNA double-strand break ends.
DR   Reactome; R-HSA-69473; G2/M DNA damage checkpoint.
DR   SIGNOR; O76064; -.
DR   UniPathway; UPA00143; -.
DR   BioGRID-ORCS; 9025; 364 hits in 1001 CRISPR screens.
DR   ChiTaRS; RNF8; human.
DR   EvolutionaryTrace; O76064; -.
DR   GeneWiki; RNF8; -.
DR   GenomeRNAi; 9025; -.
DR   Pharos; O76064; Tbio.
DR   PRO; PR:O76064; -.
DR   Proteomes; UP000005640; Chromosome 6.
DR   RNAct; O76064; protein.
DR   Bgee; ENSG00000112130; Expressed in frontal cortex and 230 other tissues.
DR   ExpressionAtlas; O76064; baseline and differential.
DR   Genevisible; O76064; HS.
DR   GO; GO:0000781; C:chromosome, telomeric region; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0030496; C:midbody; IEA:UniProtKB-SubCell.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR   GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
DR   GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR   GO; GO:0042393; F:histone binding; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0043130; F:ubiquitin binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR   GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR   GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR   GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR   GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR   GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:UniProtKB.
DR   GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
DR   GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; ISS:UniProtKB.
DR   GO; GO:0043486; P:histone exchange; ISS:UniProtKB.
DR   GO; GO:0070535; P:histone H2A K63-linked ubiquitination; IDA:UniProtKB.
DR   GO; GO:0033522; P:histone H2A ubiquitination; IDA:UniProtKB.
DR   GO; GO:0033523; P:histone H2B ubiquitination; ISS:UniProtKB.
DR   GO; GO:0036297; P:interstrand cross-link repair; TAS:UniProtKB.
DR   GO; GO:0045190; P:isotype switching; ISS:UniProtKB.
DR   GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; IMP:UniProtKB.
DR   GO; GO:0045739; P:positive regulation of DNA repair; IDA:UniProtKB.
DR   GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB.
DR   GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
DR   GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
DR   GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR   GO; GO:0010212; P:response to ionizing radiation; IDA:UniProtKB.
DR   GO; GO:0007286; P:spermatid development; ISS:UniProtKB.
DR   GO; GO:0035093; P:spermatogenesis, exchange of chromosomal proteins; ISS:UniProtKB.
DR   GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR   GO; GO:0016032; P:viral process; IEA:UniProtKB-KW.
DR   CDD; cd00060; FHA; 1.
DR   Gene3D; 3.30.40.10; -; 1.
DR   HAMAP; MF_03067; RNF8; 1.
DR   IDEAL; IID00118; -.
DR   InterPro; IPR000253; FHA_dom.
DR   InterPro; IPR017335; RNF8.
DR   InterPro; IPR008984; SMAD_FHA_dom_sf.
DR   InterPro; IPR001841; Znf_RING.
DR   InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR   InterPro; IPR017907; Znf_RING_CS.
DR   Pfam; PF00498; FHA; 1.
DR   PIRSF; PIRSF037950; E3_ubiquit_lig_RNF8; 1.
DR   SMART; SM00240; FHA; 1.
DR   SMART; SM00184; RING; 1.
DR   SUPFAM; SSF49879; SSF49879; 1.
DR   PROSITE; PS50006; FHA_DOMAIN; 1.
DR   PROSITE; PS00518; ZF_RING_1; 1.
DR   PROSITE; PS50089; ZF_RING_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cell cycle; Cell division;
KW   Chromatin regulator; Chromosome; Cytoplasm; Direct protein sequencing;
KW   DNA damage; DNA repair; Host-virus interaction; Metal-binding; Mitosis;
KW   Nucleus; Phosphoprotein; Reference proteome; Telomere; Transferase;
KW   Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger.
FT   CHAIN           1..485
FT                   /note="E3 ubiquitin-protein ligase RNF8"
FT                   /id="PRO_0000056048"
FT   DOMAIN          38..92
FT                   /note="FHA"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03067"
FT   ZN_FING         403..441
FT                   /note="RING-type"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03067"
FT   REGION          68..72
FT                   /note="Required for interaction with PIWIL1"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03067"
FT   COMPBIAS        276..345
FT                   /note="Gln-rich"
FT   MOD_RES         157
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT   VAR_SEQ         81..98
FT                   /note="SLNGVWLNRARLEPLRVY -> SFPSEKAEDFTAAGERFL (in isoform
FT                   2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_036671"
FT   VAR_SEQ         99..485
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_037831"
FT   VAR_SEQ         413..448
FT                   /note="AVTLNCAHSFCSYCINEWMKRKIECPICRKDIKSKT -> QRDCSEDRALRA
FT                   FERLPGSASLRWSGGFSLAVTPLL (in isoform 3)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_054037"
FT   VAR_SEQ         449..485
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_054038"
FT   VARIANT         162
FT                   /note="A -> T (in dbSNP:rs34338974)"
FT                   /id="VAR_052096"
FT   VARIANT         473
FT                   /note="I -> V (in dbSNP:rs1139944)"
FT                   /id="VAR_052097"
FT   MUTAGEN         42
FT                   /note="R->A: Abolishes interaction with ATM-phosphorylated
FT                   MDC1. Abolishes interaction with human herpesvirus 1 ICP0.
FT                   Abolishes recruitment to DNA damage sites after UV
FT                   irradiation, ionizing radiation, or treatment with an
FT                   alkylating agent."
FT                   /evidence="ECO:0000269|PubMed:18001824,
FT                   ECO:0000269|PubMed:21857671, ECO:0000269|PubMed:22405594,
FT                   ECO:0000269|PubMed:23233665"
FT   MUTAGEN         403
FT                   /note="C->S: Marked reduction of E2-dependent
FT                   ubiquitination of histone H2A. Loss of UBE2E2- and UBE2N-
FT                   binding. Loss of nuclear localization."
FT                   /evidence="ECO:0000269|PubMed:11322894,
FT                   ECO:0000269|PubMed:14981089, ECO:0000269|PubMed:16215985,
FT                   ECO:0000269|PubMed:18001824"
FT   MUTAGEN         405
FT                   /note="I->A: Impairs interaction with UBE2L6/UBCH8 and
FT                   ability to mediate 'Lys-48'-linked ubiquitination E3 ligase
FT                   activity, while it still catalyzes 'Lys-63'-linked
FT                   ubiquitination and still interacts with UBE2N/UBC13."
FT                   /evidence="ECO:0000269|PubMed:21911360,
FT                   ECO:0000269|PubMed:22373579, ECO:0000269|PubMed:22589545"
FT   MUTAGEN         406
FT                   /note="C->S: Abolishes ubiquitin-ligase activity."
FT                   /evidence="ECO:0000269|PubMed:21857671"
FT   MUTAGEN         443
FT                   /note="D->R: Does not affect the monomeric structure but
FT                   abolishes ability to monoubiquitinate H2A in nucleosomes."
FT                   /evidence="ECO:0000269|PubMed:22980979"
FT   CONFLICT        230
FT                   /note="V -> A (in Ref. 6; BAD96485)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        334
FT                   /note="K -> R (in Ref. 6; BAD96485)"
FT                   /evidence="ECO:0000305"
FT   STRAND          16..22
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   STRAND          29..32
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   STRAND          38..49
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   HELIX           56..58
FT                   /evidence="ECO:0007744|PDB:2CSW"
FT   STRAND          64..68
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   STRAND          74..78
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   STRAND          85..87
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   STRAND          105..109
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   STRAND          119..128
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   HELIX           129..132
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   HELIX           133..135
FT                   /evidence="ECO:0007744|PDB:2PIE"
FT   HELIX           351..400
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   TURN            404..406
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   STRAND          411..416
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   STRAND          421..423
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   HELIX           424..430
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   TURN            431..433
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   TURN            438..440
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   STRAND          447..449
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   HELIX           451..461
FT                   /evidence="ECO:0007744|PDB:4AYC"
FT   HELIX           466..480
FT                   /evidence="ECO:0007744|PDB:4AYC"
SQ   SEQUENCE   485 AA;  55518 MW;  54650B2FFC9948B1 CRC64;
     MGEPGFFVTG DRAGGRSWCL RRVGMSAGWL LLEDGCEVTV GRGFGVTYQL VSKICPLMIS
     RNHCVLKQNP EGQWTIMDNK SLNGVWLNRA RLEPLRVYSI HQGDYIQLGV PLENKENAEY
     EYEVTEEDWE TIYPCLSPKN DQMIEKNKEL RTKRKFSLDE LAGPGAEGPS NLKSKINKVS
     CESGQPVKSQ GKGEVASTPS DNLDPKLTAL EPSKTTGAPI YPGFPKVTEV HHEQKASNSS
     ASQRSLQMFK VTMSRILRLK IQMQEKHEAV MNVKKQTQKG NSKKVVQMEQ ELQDLQSQLC
     AEQAQQQARV EQLEKTFQEE EQHLQGLEIA QGEKDLKQQL AQALQEHWAL MEELNRSKKD
     FEAIIQAKNK ELEQTKEEKE KMQAQKEEVL SHMNDVLENE LQCIICSEYF IEAVTLNCAH
     SFCSYCINEW MKRKIECPIC RKDIKSKTYS LVLDNCINKM VNNLSSEVKE RRIVLIRERK
     AKRLF
//
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