RN168_HUMAN
ID RN168_HUMAN Reviewed; 571 AA.
AC Q8IYW5; Q8NA67; Q96NS4;
DT 11-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=E3 ubiquitin-protein ligase RNF168 {ECO:0000255|HAMAP-Rule:MF_03066};
DE Short=hRNF168;
DE EC=2.3.2.27 {ECO:0000255|HAMAP-Rule:MF_03066, ECO:0000269|PubMed:27153538};
DE AltName: Full=RING finger protein 168 {ECO:0000255|HAMAP-Rule:MF_03066};
DE AltName: Full=RING-type E3 ubiquitin transferase RNF168;
GN Name=RNF168 {ECO:0000255|HAMAP-Rule:MF_03066};
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 [LARGE SCALE MRNA], AND VARIANT GLN-401.
RC TISSUE=Cerebellum, and Testis;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-411; SER-414 AND SER-415, AND
RP IDENTIFICATION BY 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 [5]
RP UBIQUITIN-BINDING, CATALYTIC ACTIVITY, MIU MOTIF, SUBCELLULAR LOCATION,
RP UBIQUITINATION, AND MUTAGENESIS OF CYS-16; CYS-19; ALA-179 AND ALA-450.
RX PubMed=19500350; DOI=10.1186/1471-2199-10-55;
RA Pinato S., Scandiuzzi C., Arnaudo N., Citterio E., Gaudino G., Penengo L.;
RT "RNF168, a new RING finger, MIU-containing protein that modifies chromatin
RT by ubiquitination of histones H2A and H2AX.";
RL BMC Mol. Biol. 10:55-55(2009).
RN [6]
RP INVOLVEMENT IN RIDL, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION,
RP INTERACTION WITH UBE2N, AND MUTAGENESIS OF ALA-179 AND ALA-450.
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 [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
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 [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-411; SER-414 AND SER-415, AND
RP IDENTIFICATION BY 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 [9]
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 [10]
RP UBIQUITIN-BINDING, UMI MOTIF, SUBCELLULAR LOCATION, UBIQUITINATION, AND
RP MUTAGENESIS OF 149-LEU-LEU-150; ALA-179 AND ALA-450.
RX PubMed=21041483; DOI=10.1128/mcb.00818-10;
RA Pinato S., Gatti M., Scandiuzzi C., Confalonieri S., Penengo L.;
RT "UMI, a novel RNF168 ubiquitin binding domain involved in the DNA damage
RT signaling pathway.";
RL Mol. Cell. Biol. 31:118-126(2011).
RN [11]
RP FUNCTION.
RX PubMed=22713238; DOI=10.4161/cc.20919;
RA Gatti M., Pinato S., Maspero E., Soffientini P., Polo S., Penengo L.;
RT "A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by
RT RNF168 ubiquitin ligase.";
RL Cell Cycle 11:2538-2544(2012).
RN [12]
RP FUNCTION IN UBIQUITINATION OF KDM4A, CATALYTIC ACTIVITY, AND MUTAGENESIS OF
RP ILE-18.
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 [13]
RP SUMOYLATION.
RX PubMed=22508508; DOI=10.1083/jcb.201106152;
RA Danielsen J.R., Povlsen L.K., Villumsen B.H., Streicher W., Nilsson J.,
RA Wikstrom M., Bekker-Jensen S., Mailand N.;
RT "DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a
RT novel SUMO-binding Zinc finger.";
RL J. Cell Biol. 197:179-187(2012).
RN [14]
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 [15]
RP FUNCTION, UBIQUITIN-BINDING, LR MOTIF, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF 476-LEU-ARG-477.
RX PubMed=22742833; DOI=10.1016/j.molcel.2012.05.045;
RA Panier S., Ichijima Y., Fradet-Turcotte A., Leung C.C., Kaustov L.,
RA Arrowsmith C.H., Durocher D.;
RT "Tandem protein interaction modules organize the ubiquitin-dependent
RT response to DNA double-strand breaks.";
RL Mol. Cell 47:383-395(2012).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ARG-57.
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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-134; SER-411 AND SER-470, AND
RP IDENTIFICATION BY 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 [18]
RP FUNCTION.
RX PubMed=23760478; DOI=10.1038/nature12318;
RA Fradet-Turcotte A., Canny M.D., Escribano-Diaz C., Orthwein A., Leung C.C.,
RA Huang H., Landry M.C., Kitevski-LeBlanc J., Noordermeer S.M., Sicheri F.,
RA Durocher D.;
RT "53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark.";
RL Nature 499:50-54(2013).
RN [19]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=27153538; DOI=10.1016/j.molcel.2016.03.031;
RA Jacquet K., Fradet-Turcotte A., Avvakumov N., Lambert J.P., Roques C.,
RA Pandita R.K., Paquet E., Herst P., Gingras A.C., Pandita T.K., Legube G.,
RA Doyon Y., Durocher D., Cote J.;
RT "The TIP60 complex regulates bivalent chromatin recognition by 53BP1
RT through direct H4K20me binding and H2AK15 acetylation.";
RL Mol. Cell 62:409-421(2016).
RN [20]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-210 AND LYS-528, AND
RP IDENTIFICATION BY MASS 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 [21]
RP X-RAY CRYSTALLOGRAPHY (2.12 ANGSTROMS) OF 1-113, AND SUBUNIT.
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 required for accumulation of
CC repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to
CC amplify the RNF8-dependent histone ubiquitination. Recruited to sites
CC of DNA damage at double-strand breaks (DSBs) by binding to
CC ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A
CC ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin
CC conjugates. This leads to concentrate ubiquitinated histones H2A and
CC H2AX at DNA lesions to the threshold required for recruitment of
CC TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs)
CC sites and promotes accumulation of 'Lys-63'-linked ubiquitination of
CC 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. Also involved
CC in class switch recombination in immune system, via its role in
CC regulation of DSBs repair. Following DNA damage, promotes the
CC ubiquitination and degradation of JMJD2A/KDM4A in collaboration with
CC RNF8, leading to unmask H4K20me2 mark and promote the recruitment of
CC TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked
CC ubiquitination in vitro; possibly due to partial occlusion of the
CC UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13'
CC and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub,
CC respectively). {ECO:0000255|HAMAP-Rule:MF_03066,
CC ECO:0000269|PubMed:19203578, ECO:0000269|PubMed:19203579,
CC ECO:0000269|PubMed:20550933, ECO:0000269|PubMed:22373579,
CC ECO:0000269|PubMed:22705371, ECO:0000269|PubMed:22713238,
CC ECO:0000269|PubMed:22742833, ECO:0000269|PubMed:22980979,
CC ECO:0000269|PubMed:23760478, ECO:0000269|PubMed:27153538}.
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_03066,
CC ECO:0000269|PubMed:19203578, ECO:0000269|PubMed:19203579,
CC ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:22373579,
CC ECO:0000269|PubMed:22980979, ECO:0000269|PubMed:27153538};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000255|HAMAP-Rule:MF_03066}.
CC -!- SUBUNIT: Monomer. Interacts with UBE2N/UBC13. {ECO:0000255|HAMAP-
CC Rule:MF_03066, ECO:0000269|PubMed:19203578,
CC ECO:0000269|PubMed:22589545}.
CC -!- INTERACTION:
CC Q8IYW5; P13196: ALAS1; NbExp=3; IntAct=EBI-914207, EBI-3905054;
CC Q8IYW5; Q14203-5: DCTN1; NbExp=3; IntAct=EBI-914207, EBI-25840379;
CC Q8IYW5; P07305: H1-0; NbExp=2; IntAct=EBI-914207, EBI-725224;
CC Q8IYW5; Q9Y3C5: RNF11; NbExp=4; IntAct=EBI-914207, EBI-396669;
CC Q8IYW5; P37840: SNCA; NbExp=3; IntAct=EBI-914207, EBI-985879;
CC Q8IYW5; Q9BZR9: TRIM8; NbExp=3; IntAct=EBI-914207, EBI-2340370;
CC Q8IYW5; P61088: UBE2N; NbExp=2; IntAct=EBI-914207, EBI-1052908;
CC Q8IYW5; O76024: WFS1; NbExp=3; IntAct=EBI-914207, EBI-720609;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|HAMAP-Rule:MF_03066,
CC ECO:0000269|PubMed:19203578, ECO:0000269|PubMed:19203579,
CC ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:21041483,
CC ECO:0000269|PubMed:22742833}. Note=Localizes to double-strand breaks
CC (DSBs) sites of DNA damage. {ECO:0000255|HAMAP-Rule:MF_03066}.
CC -!- DOMAIN: The MIU motif (motif interacting with ubiquitin) mediates the
CC interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains
CC (PubMed:19500350). The UMI motif mediates interaction with ubiquitin
CC with a preference for 'Lys-63'-linked ubiquitin (PubMed:21041483). The
CC specificity for different types of ubiquitin is mediated by
CC juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR
CC motifs (LRMs) (PubMed:22742833). {ECO:0000255|HAMAP-Rule:MF_03066,
CC ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:21041483,
CC ECO:0000269|PubMed:22742833}.
CC -!- PTM: Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks
CC (DSBs). {ECO:0000255|HAMAP-Rule:MF_03066, ECO:0000269|PubMed:22508508}.
CC -!- PTM: Ubiquitinated. {ECO:0000255|HAMAP-Rule:MF_03066,
CC ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:21041483}.
CC -!- DISEASE: Riddle syndrome (RIDL) [MIM:611943]: An autosomal recessive
CC disorder characterized by increased radiosensitivity, immunodeficiency,
CC mild motor control and learning difficulties, facial dysmorphism, and
CC short stature. {ECO:0000269|PubMed:19203578}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the RNF168 family. {ECO:0000255|HAMAP-
CC Rule:MF_03066}.
CC -!- CAUTION: According to a well-established model, RNF168 cannot initiate
CC H2A 'Lys-63'-linked ubiquitination and is recruited following RNF8-
CC dependent histone ubiquitination to amplify H2A 'Lys-63'-linked
CC ubiquitination (PubMed:19500350, PubMed:19203578 and PubMed:19203579).
CC However, other data suggest that RNF168 is the priming ubiquitin ligase
CC by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal
CC histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979).
CC These data suggest that RNF168 might be recruited to DSBs sites in a
CC RNF8-dependent manner by binding to non-histone proteins ubiquitinated
CC via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is
CC then amplified by RNF8 (PubMed:22980979). Additional evidence is
CC however required to confirm these data. {ECO:0000255|HAMAP-
CC Rule:MF_03066, ECO:0000305|PubMed:22980979}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC04060.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK054732; BAB70801.1; -; mRNA.
DR EMBL; AK093113; BAC04060.1; ALT_INIT; mRNA.
DR EMBL; AC092933; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC117490; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC033791; AAH33791.1; -; mRNA.
DR CCDS; CCDS3317.1; -.
DR RefSeq; NP_689830.2; NM_152617.3.
DR PDB; 3L11; X-ray; 2.12 A; A=1-113.
DR PDB; 4GB0; X-ray; 2.60 A; A=1-111.
DR PDB; 5XIS; X-ray; 1.78 A; A/D=110-188.
DR PDB; 5XIT; X-ray; 2.25 A; A/E=113-188.
DR PDB; 5XIU; X-ray; 1.80 A; A=419-462.
DR PDB; 5YDK; X-ray; 2.50 A; A/F/G/L=113-194.
DR PDBsum; 3L11; -.
DR PDBsum; 4GB0; -.
DR PDBsum; 5XIS; -.
DR PDBsum; 5XIT; -.
DR PDBsum; 5XIU; -.
DR PDBsum; 5YDK; -.
DR AlphaFoldDB; Q8IYW5; -.
DR SMR; Q8IYW5; -.
DR BioGRID; 127922; 89.
DR DIP; DIP-37451N; -.
DR IntAct; Q8IYW5; 34.
DR MINT; Q8IYW5; -.
DR STRING; 9606.ENSP00000320898; -.
DR iPTMnet; Q8IYW5; -.
DR PhosphoSitePlus; Q8IYW5; -.
DR BioMuta; RNF168; -.
DR DMDM; 74762499; -.
DR EPD; Q8IYW5; -.
DR jPOST; Q8IYW5; -.
DR MassIVE; Q8IYW5; -.
DR MaxQB; Q8IYW5; -.
DR PaxDb; Q8IYW5; -.
DR PeptideAtlas; Q8IYW5; -.
DR PRIDE; Q8IYW5; -.
DR ProteomicsDB; 71253; -.
DR Antibodypedia; 33941; 235 antibodies from 30 providers.
DR CPTC; Q8IYW5; 1 antibody.
DR DNASU; 165918; -.
DR Ensembl; ENST00000318037.3; ENSP00000320898.3; ENSG00000163961.4.
DR GeneID; 165918; -.
DR KEGG; hsa:165918; -.
DR MANE-Select; ENST00000318037.3; ENSP00000320898.3; NM_152617.4; NP_689830.2.
DR UCSC; uc003fwq.4; human.
DR CTD; 165918; -.
DR DisGeNET; 165918; -.
DR GeneCards; RNF168; -.
DR HGNC; HGNC:26661; RNF168.
DR HPA; ENSG00000163961; Low tissue specificity.
DR MalaCards; RNF168; -.
DR MIM; 611943; phenotype.
DR MIM; 612688; gene.
DR neXtProt; NX_Q8IYW5; -.
DR OpenTargets; ENSG00000163961; -.
DR Orphanet; 420741; RIDDLE syndrome.
DR PharmGKB; PA134945219; -.
DR VEuPathDB; HostDB:ENSG00000163961; -.
DR eggNOG; KOG4159; Eukaryota.
DR GeneTree; ENSGT00940000153680; -.
DR HOGENOM; CLU_030653_1_0_1; -.
DR InParanoid; Q8IYW5; -.
DR OMA; TILQMFK; -.
DR OrthoDB; 458276at2759; -.
DR PhylomeDB; Q8IYW5; -.
DR TreeFam; TF332796; -.
DR PathwayCommons; Q8IYW5; -.
DR Reactome; R-HSA-3108214; SUMOylation of DNA damage response and repair proteins.
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 SignaLink; Q8IYW5; -.
DR SIGNOR; Q8IYW5; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 165918; 358 hits in 1127 CRISPR screens.
DR ChiTaRS; RNF168; human.
DR EvolutionaryTrace; Q8IYW5; -.
DR GenomeRNAi; 165918; -.
DR Pharos; Q8IYW5; Tbio.
DR PRO; PR:Q8IYW5; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q8IYW5; protein.
DR Bgee; ENSG00000163961; Expressed in sperm and 183 other tissues.
DR ExpressionAtlas; Q8IYW5; baseline and differential.
DR Genevisible; Q8IYW5; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:MGI.
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:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031491; F:nucleosome binding; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
DR GO; GO:0070535; P:histone H2A K63-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0035518; P:histone H2A monoubiquitination; IDA:UniProtKB.
DR GO; GO:0036351; P:histone H2A-K13 ubiquitination; IDA:UniProtKB.
DR GO; GO:0036352; P:histone H2A-K15 ubiquitination; IDA: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:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0010212; P:response to ionizing radiation; IDA:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR Gene3D; 3.30.40.10; -; 1.
DR HAMAP; MF_03066; RNF168; 1.
DR InterPro; IPR034725; RNF168.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chromatin regulator; DNA damage; DNA repair; Isopeptide bond;
KW Metal-binding; Nucleus; Phosphoprotein; Reference proteome; Transferase;
KW Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..571
FT /note="E3 ubiquitin-protein ligase RNF168"
FT /id="PRO_0000245596"
FT ZN_FING 16..55
FT /note="RING-type"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT REGION 151..174
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 191..292
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 390..422
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 459..560
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 110..128
FT /note="LR motif 1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 143..151
FT /note="UMI motif"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 168..191
FT /note="MIU motif 1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 439..462
FT /note="MIU motif 2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT MOTIF 466..477
FT /note="LR motif 2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03066"
FT COMPBIAS 191..205
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 206..221
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 222..241
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 243..268
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 269..289
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 390..416
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 459..473
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 489..522
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 70
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80XJ2"
FT MOD_RES 134
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 197
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:B2RYR0"
FT MOD_RES 362
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:B2RYR0"
FT MOD_RES 411
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT MOD_RES 414
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332"
FT MOD_RES 415
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332"
FT MOD_RES 470
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 210
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 528
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VARIANT 387
FT /note="K -> R (in dbSNP:rs35774921)"
FT /id="VAR_034466"
FT VARIANT 401
FT /note="P -> Q (in dbSNP:rs3796129)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_026997"
FT VARIANT 413
FT /note="E -> K (in dbSNP:rs6790173)"
FT /id="VAR_052110"
FT MUTAGEN 16
FT /note="C->S: Does not affect ability to bind ubiquitin and
FT localization to DSBs sites, while it abolishes E3 ligase
FT activity; when associated with S-19."
FT /evidence="ECO:0000269|PubMed:19500350"
FT MUTAGEN 18
FT /note="I->A: Abolishes ability to ubiquitinate KDM4A."
FT /evidence="ECO:0000269|PubMed:22373579"
FT MUTAGEN 19
FT /note="C->S: Does not affect ability to bind ubiquitin and
FT localization to DSBs sites, while it abolishes E3 ligase
FT activity; when associated with S-16."
FT /evidence="ECO:0000269|PubMed:19500350"
FT MUTAGEN 57
FT /note="R->D: Does not affect the monomeric structure but
FT abolishes ability to monoubiquitinate H2A in nucleosomes."
FT /evidence="ECO:0000269|PubMed:22980979"
FT MUTAGEN 149..150
FT /note="LL->AA: Impaired ability to bind ubiquitin."
FT /evidence="ECO:0000269|PubMed:21041483"
FT MUTAGEN 179
FT /note="A->G: Impairs ability to form foci following
FT ionizing radiation and impaired binding to 'Lys-63'-linked
FT ubiquitin."
FT /evidence="ECO:0000269|PubMed:19203578,
FT ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:21041483"
FT MUTAGEN 450
FT /note="A->G: Still able to bind 'Lys-63'-linked ubiquitin."
FT /evidence="ECO:0000269|PubMed:19203578,
FT ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:21041483"
FT MUTAGEN 476..477
FT /note="LR->AA: Does not affect ubiquitin-binding but
FT impairs recruitment to DSBs."
FT /evidence="ECO:0000269|PubMed:22742833"
FT CONFLICT 9
FT /note="P -> L (in Ref. 1; BAB70801)"
FT /evidence="ECO:0000305"
FT HELIX 11..14
FT /evidence="ECO:0007829|PDB:3L11"
FT TURN 17..19
FT /evidence="ECO:0007829|PDB:3L11"
FT STRAND 24..28
FT /evidence="ECO:0007829|PDB:4GB0"
FT STRAND 34..36
FT /evidence="ECO:0007829|PDB:4GB0"
FT HELIX 37..43
FT /evidence="ECO:0007829|PDB:3L11"
FT TURN 44..48
FT /evidence="ECO:0007829|PDB:3L11"
FT TURN 52..54
FT /evidence="ECO:0007829|PDB:3L11"
FT HELIX 59..67
FT /evidence="ECO:0007829|PDB:3L11"
FT HELIX 74..83
FT /evidence="ECO:0007829|PDB:3L11"
FT HELIX 85..93
FT /evidence="ECO:0007829|PDB:3L11"
FT HELIX 115..187
FT /evidence="ECO:0007829|PDB:5XIS"
FT HELIX 419..455
FT /evidence="ECO:0007829|PDB:5XIU"
SQ SEQUENCE 571 AA; 65020 MW; 51E16DA92BA654C1 CRC64;
MALPKDAIPS LSECQCGICM EILVEPVTLP CNHTLCKPCF QSTVEKASLC CPFCRRRVSS
WTRYHTRRNS LVNVELWTII QKHYPRECKL RASGQESEEV ADDYQPVRLL SKPGELRREY
EEEISKVAAE RRASEEEENK ASEEYIQRLL AEEEEEEKRQ AEKRRRAMEE QLKSDEELAR
KLSIDINNFC EGSISASPLN SRKSDPVTPK SEKKSKNKQR NTGDIQKYLT PKSQFGSASH
SEAVQEVRKD SVSKDIDSSD RKSPTGQDTE IEDMPTLSPQ ISLGVGEQGA DSSIESPMPW
LCACGAEWYH EGNVKTRPSN HGKELCVLSH ERPKTRVPYS KETAVMPCGR TESGCAPTSG
VTQTNGNNTG ETENEESCLL ISKEISKRKN QESSFEAVKD PCFSAKRRKV SPESSPDQEE
TEINFTQKLI DLEHLLFERH KQEEQDRLLA LQLQKEVDKE QMVPNRQKGS PDEYHLRATS
SPPDKVLNGQ RKNPKDGNFK RQTHTKHPTP ERGSRDKNRQ VSLKMQLKQS VNRRKMPNST
RDHCKVSKSA HSLQPSISQK SVFQMFQRCT K
