TONSL_HUMAN
ID TONSL_HUMAN Reviewed; 1378 AA.
AC Q96HA7; B5MDP0; C9JKB1; C9JNV8; Q13006; Q9UGJ2;
DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot.
DT 08-APR-2008, sequence version 2.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=Tonsoku-like protein {ECO:0000303|PubMed:21055983};
DE AltName: Full=Inhibitor of kappa B-related protein {ECO:0000303|PubMed:7738005};
DE Short=I-kappa-B-related protein {ECO:0000303|PubMed:7738005};
DE Short=IkappaBR {ECO:0000303|PubMed:7738005};
DE AltName: Full=NF-kappa-B inhibitor-like protein 2;
DE AltName: Full=Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 2;
GN Name=TONSL {ECO:0000303|PubMed:21055983, ECO:0000312|HGNC:HGNC:7801};
GN Synonyms=IKBR {ECO:0000303|PubMed:7738005}, NFKBIL2;
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 [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND VARIANT SER-493.
RC TISSUE=Cervix carcinoma;
RX PubMed=7738005; DOI=10.1074/jbc.270.18.10680;
RA Ray P., Zhang D.H., Elias J.A., Ray A.;
RT "Cloning of a differentially expressed I kappa B-related protein.";
RL J. Biol. Chem. 270:10680-10685(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 6-1378 (ISOFORM 1), AND VARIANT
RP VAL-714.
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 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 64-671, AND VARIANT SER-493.
RX PubMed=11246458; DOI=10.1017/s0003480000007910;
RA Norman D.A., Barton P.J.;
RT "Isolation, sequence, and chromosomal localisation of the human IkappaBR
RT gene (NFKBIL2).";
RL Ann. Hum. Genet. 64:15-23(2000).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=9242696; DOI=10.1074/jbc.272.32.20191;
RA Ray P., Yang L., Zhang D.H., Ghosh S.K., Ray A.;
RT "Selective up-regulation of cytokine-induced RANTES gene expression in lung
RT epithelial cells by overexpression of IkappaBR.";
RL J. Biol. Chem. 272:20191-20197(1997).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-719, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [7]
RP FUNCTION, AND IDENTIFICATION IN THE MMS22L-TONSL COMPLEX.
RX PubMed=21113133; DOI=10.1038/emboj.2010.304;
RA Piwko W., Olma M.H., Held M., Bianco J.N., Pedrioli P.G., Hofmann K.,
RA Pasero P., Gerlich D.W., Peter M.;
RT "RNAi-based screening identifies the Mms22L-Nfkbil2 complex as a novel
RT regulator of DNA replication in human cells.";
RL EMBO J. 29:4210-4222(2010).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN THE MMS22L-TONSL
RP COMPLEX.
RX PubMed=21055983; DOI=10.1016/j.molcel.2010.10.024;
RA O'Donnell L., Panier S., Wildenhain J., Tkach J.M., Al-Hakim A.,
RA Landry M.C., Escribano-Diaz C., Szilard R.K., Young J.T., Munro M.,
RA Canny M.D., Kolas N.K., Zhang W., Harding S.M., Ylanko J., Mendez M.,
RA Mullin M., Sun T., Habermann B., Datti A., Bristow R.G., Gingras A.C.,
RA Tyers M.D., Brown G.W., Durocher D.;
RT "The MMS22L-TONSL complex mediates recovery from replication stress and
RT homologous recombination.";
RL Mol. Cell 40:619-631(2010).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION IN THE MMS22L-TONSL COMPLEX,
RP AND DOMAIN.
RX PubMed=21055984; DOI=10.1016/j.molcel.2010.10.023;
RA Duro E., Lundin C., Ask K., Sanchez-Pulido L., MacArtney T.J., Toth R.,
RA Ponting C.P., Groth A., Helleday T., Rouse J.;
RT "Identification of the MMS22L-TONSL complex that promotes homologous
RT recombination.";
RL Mol. Cell 40:632-644(2010).
RN [10]
RP FUNCTION, AND IDENTIFICATION IN THE MMS22L-TONSL COMPLEX.
RX PubMed=21055985; DOI=10.1016/j.molcel.2010.10.022;
RA O'Connell B.C., Adamson B., Lydeard J.R., Sowa M.E., Ciccia A.,
RA Bredemeyer A.L., Schlabach M., Gygi S.P., Elledge S.J., Harper J.W.;
RT "A genome-wide camptothecin sensitivity screen identifies a mammalian
RT MMS22L-NFKBIL2 complex required for genomic stability.";
RL Mol. Cell 40:645-657(2010).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-719, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
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 [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-719, 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 [14]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MCM5.
RX PubMed=26527279; DOI=10.1016/j.molcel.2015.08.005;
RA Campos E.I., Smits A.H., Kang Y.H., Landry S., Escobar T.M., Nayak S.,
RA Ueberheide B.M., Durocher D., Vermeulen M., Hurwitz J., Reinberg D.;
RT "Analysis of the histone H3.1 interactome: a suitable chaperone for the
RT right event.";
RL Mol. Cell 60:697-709(2015).
RN [15]
RP FUNCTION.
RX PubMed=27797818; DOI=10.15252/embj.201593132;
RA Piwko W., Mlejnkova L.J., Mutreja K., Ranjha L., Stafa D., Smirnov A.,
RA Brodersen M.M., Zellweger R., Sturzenegger A., Janscak P., Lopes M.,
RA Peter M., Cejka P.;
RT "The MMS22L-TONSL heterodimer directly promotes RAD51-dependent
RT recombination upon replication stress.";
RL EMBO J. 35:2584-2601(2016).
RN [16]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=29478807; DOI=10.1016/j.molcel.2018.01.031;
RA Huang T.H., Fowler F., Chen C.C., Shen Z.J., Sleckman B., Tyler J.K.;
RT "The histone chaperones ASF1 and CAF-1 promote MMS22L-TONSL-mediated Rad51
RT loading onto ssDNA during homologous recombination in human cells.";
RL Mol. Cell 69:879-892(2018).
RN [17]
RP INTERACTION WITH DNJC9; H3.1 AND H3.1T.
RX PubMed=33857403; DOI=10.1016/j.molcel.2021.03.041;
RA Hammond C.M., Bao H., Hendriks I.A., Carraro M., Garcia-Nieto A., Liu Y.,
RA Reveron-Gomez N., Spanos C., Chen L., Rappsilber J., Nielsen M.L.,
RA Patel D.J., Huang H., Groth A.;
RT "DNAJC9 integrates heat shock molecular chaperones into the histone
RT chaperone network.";
RL Mol. Cell 0:0-0(2021).
RN [18] {ECO:0007744|PDB:5JA4}
RP X-RAY CRYSTALLOGRAPHY (2.42 ANGSTROMS) OF 512-692 IN COMPLEX WITH HISTONE
RP H4, FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HISTONE H4K20ME0,
RP IDENTIFICATION IN THE MMS22L-TONSL COMPLEX, AND MUTAGENESIS OF GLU-530;
RP ASP-559; TRP-563; GLU-568; ASN-571 AND ASP-604.
RX PubMed=27338793; DOI=10.1038/nature18312;
RA Saredi G., Huang H., Hammond C.M., Alabert C., Bekker-Jensen S., Forne I.,
RA Reveron-Gomez N., Foster B.M., Mlejnkova L., Bartke T., Cejka P.,
RA Mailand N., Imhof A., Patel D.J., Groth A.;
RT "H4K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L
RT DNA repair complex.";
RL Nature 534:714-718(2016).
RN [19]
RP VARIANTS SEMDSP 110-TRP--LEU-1378 DEL; 154-GLN--LEU-1378 DEL; LYS-199;
RP LYS-487; LYS-494; LEU-613; MET-653; 713-GLN--LEU-1378 DEL;
RP 803-GLN--LEU-1378 DEL; TRP-934 AND PRO-1197, AND INVOLVEMENT IN SEMDSP.
RX PubMed=30773277; DOI=10.1016/j.ajhg.2019.01.007;
RG University of Washington Center for Mendelian Genomics;
RG Undiagnosed Diseases Network;
RA Burrage L.C., Reynolds J.J., Baratang N.V., Phillips J.B., Wegner J.,
RA McFarquhar A., Higgs M.R., Christiansen A.E., Lanza D.G., Seavitt J.R.,
RA Jain M., Li X., Parry D.A., Raman V., Chitayat D., Chinn I.K.,
RA Bertuch A.A., Karaviti L., Schlesinger A.E., Earl D., Bamshad M.,
RA Savarirayan R., Doddapaneni H., Muzny D., Jhangiani S.N., Eng C.M.,
RA Gibbs R.A., Bi W., Emrick L., Rosenfeld J.A., Postlethwait J.,
RA Westerfield M., Dickinson M.E., Beaudet A.L., Ranza E., Huber C.,
RA Cormier-Daire V., Shen W., Mao R., Heaney J.D., Orange J.S., Bertola D.,
RA Yamamoto G.L., Baratela W.A.R., Butler M.G., Ali A., Adeli M., Cohn D.H.,
RA Krakow D., Jackson A.P., Lees M., Offiah A.C., Carlston C.M., Carey J.C.,
RA Stewart G.S., Bacino C.A., Campeau P.M., Lee B.;
RT "Bi-allelic variants in TONSL cause sponastrime dysplasia and a spectrum of
RT skeletal dysplasia phenotypes.";
RL Am. J. Hum. Genet. 104:422-438(2019).
RN [20]
RP INVOLVEMENT IN SEMDSP, FUNCTION, VARIANTS SEMDSP HIS-42; ASN-174; HIS-364;
RP LYS-487; 511-GLN--LEU-1378 DEL; LYS-539; GLN-558; TRP-934;
RP 969-TYR--LEU-1378 DEL; ARG-973 AND GLN-1288, AND CHARACTERIZATION OF
RP VARIANTS SEMDSP ASN-174; HIS-364; LYS-539; GLN-558; TRP-934 AND ARG-973.
RX PubMed=30773278; DOI=10.1016/j.ajhg.2019.01.009;
RA Chang H.R., Cho S.Y., Lee J.H., Lee E., Seo J., Lee H.R., Cavalcanti D.P.,
RA Maekitie O., Valta H., Girisha K.M., Lee C., Neethukrishna K.,
RA Bhavani G.S., Shukla A., Nampoothiri S., Phadke S.R., Park M.J.,
RA Ikegawa S., Wang Z., Higgs M.R., Stewart G.S., Jung E., Lee M.S.,
RA Park J.H., Lee E.A., Kim H., Myung K., Jeon W., Lee K., Kim D., Kim O.H.,
RA Choi M., Lee H.W., Kim Y., Cho T.J.;
RT "Hypomorphic mutations in TONSL cause sponastrime dysplasia.";
RL Am. J. Hum. Genet. 104:439-453(2019).
RN [21]
RP VARIANTS SEMDSP ARG-430 AND ARG-1090.
RX PubMed=32959051; DOI=10.1093/hmg/ddaa195;
RA Micale L., Cialfi S., Fusco C., Cinque L., Castellana S., Biagini T.,
RA Talora C., Notarangelo A., Bisceglia L., Taruscio D., Salvatore M.,
RA Castori M.;
RT "Novel TONSL variants cause SPONASTRIME dysplasia and associate with
RT spontaneous chromosome breaks, defective cell proliferation and
RT apoptosis.";
RL Hum. Mol. Genet. 29:3122-3131(2020).
CC -!- FUNCTION: Component of the MMS22L-TONSL complex, a complex that
CC promotes homologous recombination-mediated repair of double-strand
CC breaks (DSBs) at stalled or collapsed replication forks
CC (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:21113133,
CC PubMed:26527279, PubMed:27797818, PubMed:29478807, PubMed:27338793,
CC PubMed:30773278). The MMS22L-TONSL complex is required to maintain
CC genome integrity during DNA replication (PubMed:21055983,
CC PubMed:21055984, PubMed:21055985). It mediates the assembly of RAD51
CC filaments on single-stranded DNA (ssDNA): the MMS22L-TONSL complex is
CC recruited to DSBs following histone replacement by histone chaperones
CC and eviction of the replication protein A complex (RPA/RP-A) from DSBs
CC (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:27797818,
CC PubMed:29478807). Following recruitment to DSBs, the TONSL-MMS22L
CC complex promotes recruitment of RAD51 filaments and subsequent
CC homologous recombination (PubMed:27797818, PubMed:29478807). Within the
CC complex, TONSL acts as histone reader, which recognizes and binds newly
CC synthesized histones following their replacement by histone chaperones
CC (PubMed:29478807, PubMed:27338793). Specifically binds histone H4
CC lacking methylation at 'Lys-20' (H4K20me0) and histone H3.1
CC (PubMed:27338793). {ECO:0000269|PubMed:21055983,
CC ECO:0000269|PubMed:21055984, ECO:0000269|PubMed:21055985,
CC ECO:0000269|PubMed:21113133, ECO:0000269|PubMed:26527279,
CC ECO:0000269|PubMed:27338793, ECO:0000269|PubMed:27797818,
CC ECO:0000269|PubMed:29478807, ECO:0000269|PubMed:30773278}.
CC -!- SUBUNIT: Component of the MMS22L-TONSL complex, a complex at least
CC composed of MMS22L and TONSL/NFKBIL2 (PubMed:21055983, PubMed:21055984,
CC PubMed:21055985, PubMed:21113133, PubMed:27338793). Interacts with the
CC MCM complex, the FACT complex and the RPA complex (PubMed:21055983,
CC PubMed:21055984, PubMed:26527279). Interacts with MCM5; the interaction
CC is direct (PubMed:26527279). Binds histones, with a strong preference
CC for histone H3.1 (histones H3.1 and H3-4/H3.1t) (PubMed:21055983,
CC PubMed:21055984, PubMed:26527279, PubMed:33857403). Interacts (via ANK
CC repeats) with histone H4; specifically binds histone H4 lacking
CC methylation at 'Lys-20' (H4K20me0) (PubMed:27338793). May interact with
CC DNAJC9; the interaction seems to be histone-dependent
CC (PubMed:33857403). {ECO:0000269|PubMed:21055983,
CC ECO:0000269|PubMed:21055984, ECO:0000269|PubMed:21055985,
CC ECO:0000269|PubMed:21113133, ECO:0000269|PubMed:26527279,
CC ECO:0000269|PubMed:27338793, ECO:0000269|PubMed:33857403}.
CC -!- INTERACTION:
CC Q96HA7; Q6ZRQ5: MMS22L; NbExp=5; IntAct=EBI-1052467, EBI-718662;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21055983,
CC ECO:0000269|PubMed:21055984, ECO:0000269|PubMed:9242696}. Chromosome
CC {ECO:0000269|PubMed:21055983, ECO:0000269|PubMed:21055984,
CC ECO:0000269|PubMed:26527279, ECO:0000269|PubMed:27338793,
CC ECO:0000269|PubMed:29478807}. Cytoplasm {ECO:0000269|PubMed:7738005}.
CC Note=Mainly nuclear (PubMed:21055983, PubMed:21055984). Localizes to
CC DNA damage sites, accumulates at stressed replication forks
CC (PubMed:21055983, PubMed:21055984, PubMed:26527279, PubMed:27338793).
CC Recruited to stalled or collapsed replication forks following histone
CC replacement by histone chaperones ASF1A and the CAF-1 complex: TONSL
CC acts as histone reader that recognizes and binds newly synthesized
CC histones (PubMed:29478807). {ECO:0000269|PubMed:21055983,
CC ECO:0000269|PubMed:21055984, ECO:0000269|PubMed:26527279,
CC ECO:0000269|PubMed:27338793, ECO:0000269|PubMed:29478807}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96HA7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96HA7-2; Sequence=VSP_032686;
CC -!- TISSUE SPECIFICITY: Expressed in heart, skeletal muscle and tracheal
CC epithelial cells. {ECO:0000269|PubMed:7738005}.
CC -!- DOMAIN: The ANK repeats mediate the interaction with the MCM complex
CC and histones, while the LRR repeats mediate the interaction with
CC MMS22L. {ECO:0000269|PubMed:21055984}.
CC -!- DISEASE: Spondyloepimetaphyseal dysplasia, sponastrime type (SEMDSP)
CC [MIM:271510]: An autosomal recessive bone disease characterized by
CC spine abnormalities, mid-face hypoplasia with a depressed nasal bridge,
CC and striation of the metaphyses. Additional features include
CC disproportionate short stature with exaggerated lumbar lordosis,
CC scoliosis, coxa vara, limited elbow extension, small dysplastic
CC epiphyses, childhood cataracts, short dental roots, and
CC hypogammaglobulinemia. Disease severity and clinical manifestations are
CC variable. Some patients have intellectual disability.
CC {ECO:0000269|PubMed:30773277, ECO:0000269|PubMed:30773278,
CC ECO:0000269|PubMed:32959051}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the Tonsoku family. {ECO:0000305}.
CC -!- CAUTION: Was reported to share sequence similarities with IKBKB and
CC therefore named 'NF-kappa-B inhibitor-like protein 2' (PubMed:7738005).
CC However, the sequence similarity is remote and effects as regulator of
CC NF-kappa-B are probably indirect and require additional evidence
CC (PubMed:9242696). {ECO:0000305|PubMed:7738005,
CC ECO:0000305|PubMed:9242696}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA85819.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=AAH08782.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAB63467.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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; U16258; AAA85819.1; ALT_FRAME; mRNA.
DR EMBL; AC084125; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF205589; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC008782; AAH08782.1; ALT_INIT; mRNA.
DR EMBL; AJ249601; CAB63467.1; ALT_SEQ; Genomic_DNA.
DR CCDS; CCDS34968.2; -. [Q96HA7-1]
DR PIR; A56429; A56429.
DR RefSeq; NP_038460.4; NM_013432.4. [Q96HA7-1]
DR PDB; 5JA4; X-ray; 2.42 A; D=512-692.
DR PDBsum; 5JA4; -.
DR AlphaFoldDB; Q96HA7; -.
DR SMR; Q96HA7; -.
DR BioGRID; 110863; 97.
DR IntAct; Q96HA7; 32.
DR MINT; Q96HA7; -.
DR STRING; 9606.ENSP00000386239; -.
DR iPTMnet; Q96HA7; -.
DR MetOSite; Q96HA7; -.
DR PhosphoSitePlus; Q96HA7; -.
DR BioMuta; TONSL; -.
DR DMDM; 182662416; -.
DR EPD; Q96HA7; -.
DR jPOST; Q96HA7; -.
DR MassIVE; Q96HA7; -.
DR MaxQB; Q96HA7; -.
DR PaxDb; Q96HA7; -.
DR PeptideAtlas; Q96HA7; -.
DR PRIDE; Q96HA7; -.
DR ProteomicsDB; 76723; -. [Q96HA7-1]
DR ProteomicsDB; 76724; -. [Q96HA7-2]
DR Antibodypedia; 14893; 207 antibodies from 21 providers.
DR DNASU; 4796; -.
DR Ensembl; ENST00000409379.8; ENSP00000386239.3; ENSG00000160949.18. [Q96HA7-1]
DR GeneID; 4796; -.
DR KEGG; hsa:4796; -.
DR MANE-Select; ENST00000409379.8; ENSP00000386239.3; NM_013432.5; NP_038460.4.
DR UCSC; uc011llg.3; human. [Q96HA7-1]
DR CTD; 4796; -.
DR DisGeNET; 4796; -.
DR GeneCards; TONSL; -.
DR HGNC; HGNC:7801; TONSL.
DR HPA; ENSG00000160949; Tissue enhanced (bone).
DR MalaCards; TONSL; -.
DR MIM; 271510; phenotype.
DR MIM; 604546; gene.
DR neXtProt; NX_Q96HA7; -.
DR OpenTargets; ENSG00000160949; -.
DR Orphanet; 93357; SPONASTRIME dysplasia.
DR PharmGKB; PA31605; -.
DR VEuPathDB; HostDB:ENSG00000160949; -.
DR eggNOG; KOG0504; Eukaryota.
DR eggNOG; KOG4308; Eukaryota.
DR GeneTree; ENSGT00940000160188; -.
DR HOGENOM; CLU_002128_0_0_1; -.
DR InParanoid; Q96HA7; -.
DR OMA; AEICEQQ; -.
DR OrthoDB; 56880at2759; -.
DR PhylomeDB; Q96HA7; -.
DR TreeFam; TF326440; -.
DR PathwayCommons; Q96HA7; -.
DR SignaLink; Q96HA7; -.
DR BioGRID-ORCS; 4796; 785 hits in 1088 CRISPR screens.
DR ChiTaRS; TONSL; human.
DR GenomeRNAi; 4796; -.
DR Pharos; Q96HA7; Tbio.
DR PRO; PR:Q96HA7; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q96HA7; protein.
DR Bgee; ENSG00000160949; Expressed in mucosa of transverse colon and 94 other tissues.
DR ExpressionAtlas; Q96HA7; baseline and differential.
DR Genevisible; Q96HA7; HS.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0016604; C:nuclear body; IDA:HPA.
DR GO; GO:0043596; C:nuclear replication fork; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0042393; F:histone binding; IDA:UniProtKB.
DR GO; GO:0140566; F:histone reader activity; IDA:UniProtKB.
DR GO; GO:0000724; P:double-strand break repair via homologous recombination; IDA:UniProtKB.
DR GO; GO:0031297; P:replication fork processing; IMP:UniProtKB.
DR Gene3D; 1.25.40.10; -; 2.
DR Gene3D; 1.25.40.20; -; 1.
DR Gene3D; 3.80.10.10; -; 3.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR011990; TPR-like_helical_dom_sf.
DR InterPro; IPR019734; TPR_repeat.
DR Pfam; PF12796; Ank_2; 1.
DR Pfam; PF13516; LRR_6; 2.
DR Pfam; PF13181; TPR_8; 1.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 3.
DR SMART; SM00028; TPR; 7.
DR SUPFAM; SSF48403; SSF48403; 1.
DR SUPFAM; SSF48452; SSF48452; 3.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 3.
DR PROSITE; PS50293; TPR_REGION; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ANK repeat; Chromatin regulator;
KW Chromosome; Cytoplasm; Disease variant; DNA damage; DNA repair; Dwarfism;
KW Leucine-rich repeat; Methylation; Nucleus; Phosphoprotein;
KW Reference proteome; Repeat; TPR repeat.
FT CHAIN 1..1378
FT /note="Tonsoku-like protein"
FT /id="PRO_0000326634"
FT REPEAT 27..60
FT /note="TPR 1"
FT REPEAT 67..100
FT /note="TPR 2"
FT REPEAT 107..147
FT /note="TPR 3"
FT REPEAT 162..195
FT /note="TPR 4"
FT REPEAT 202..235
FT /note="TPR 5"
FT REPEAT 242..275
FT /note="TPR 6"
FT REPEAT 311..344
FT /note="TPR 7"
FT REPEAT 352..385
FT /note="TPR 8"
FT REPEAT 528..557
FT /note="ANK 1"
FT REPEAT 561..590
FT /note="ANK 2"
FT REPEAT 597..626
FT /note="ANK 3"
FT REPEAT 1069..1093
FT /note="LRR 1"
FT REPEAT 1097..1122
FT /note="LRR 2"
FT REPEAT 1128..1151
FT /note="LRR 3"
FT REPEAT 1188..1212
FT /note="LRR 4"
FT REPEAT 1247..1270
FT /note="LRR 5"
FT REPEAT 1275..1300
FT /note="LRR 6"
FT REPEAT 1331..1354
FT /note="LRR 7"
FT REGION 475..524
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 667..789
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 842..933
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 485..505
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 506..524
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 669..690
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 735..750
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 862..876
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 881..919
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 719
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 797
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q6NZL6"
FT VAR_SEQ 631..641
FT /note="GLSPLETLQQW -> ASARWRRCSSG (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:7738005"
FT /id="VSP_032686"
FT VARIANT 42
FT /note="R -> H (in SEMDSP; unknown pathological
FT significance; dbSNP:rs778155094)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083007"
FT VARIANT 110..1378
FT /note="Missing (in SEMDSP; disease phenotype includes
FT immunologic and hematologic abnormalities)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083008"
FT VARIANT 154..1378
FT /note="Missing (in SEMDSP)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083009"
FT VARIANT 174
FT /note="S -> N (in SEMDSP; decreased function in double-
FT strand break repair via homologous recombination)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083010"
FT VARIANT 199
FT /note="E -> K (in SEMDSP; disease phenotype includes
FT immunologic and hematologic abnormalities;
FT dbSNP:rs1335783881)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083011"
FT VARIANT 364
FT /note="D -> H (in SEMDSP; unknown pathological
FT significance; decreased function in double-strand break
FT repair via homologous recombination)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083012"
FT VARIANT 430
FT /note="Q -> R (in SEMDSP; unknown pathological
FT significance; genomic instability; when associated with R-
FT 1090)"
FT /evidence="ECO:0000269|PubMed:32959051"
FT /id="VAR_086303"
FT VARIANT 487
FT /note="E -> K (in SEMDSP; unknown pathological
FT significance; dbSNP:rs563710728)"
FT /evidence="ECO:0000269|PubMed:30773277,
FT ECO:0000269|PubMed:30773278"
FT /id="VAR_083013"
FT VARIANT 488
FT /note="V -> M (in dbSNP:rs2229314)"
FT /id="VAR_042411"
FT VARIANT 493
FT /note="G -> S (in dbSNP:rs2229315)"
FT /evidence="ECO:0000269|PubMed:11246458,
FT ECO:0000269|PubMed:7738005"
FT /id="VAR_042412"
FT VARIANT 494
FT /note="E -> K (in SEMDSP; unknown pathological
FT significance; dbSNP:rs775551492)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083014"
FT VARIANT 511..1378
FT /note="Missing (in SEMDSP)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083015"
FT VARIANT 539
FT /note="E -> K (in SEMDSP; decreased function in double-
FT strand break repair via homologous recombination;
FT dbSNP:rs370196996)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083016"
FT VARIANT 558
FT /note="R -> Q (in SEMDSP; decreased function in double-
FT strand break repair via homologous recombination; decreased
FT protein amount in patient cells; dbSNP:rs777654833)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083017"
FT VARIANT 613
FT /note="V -> L (in SEMDSP; disease phenotype includes
FT immunologic and hematologic abnormalities; unknown
FT pathological significance; dbSNP:rs778625348)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083018"
FT VARIANT 653
FT /note="T -> M (in SEMDSP; disease phenotype includes
FT primary aphakia and absent pupils; dbSNP:rs755055463)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083019"
FT VARIANT 713..1378
FT /note="Missing (in SEMDSP; disease phenotype includes
FT primary aphakia and absent pupils)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083020"
FT VARIANT 714
FT /note="A -> V (in dbSNP:rs7830832)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_042413"
FT VARIANT 803..1378
FT /note="Missing (in SEMDSP)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083021"
FT VARIANT 934
FT /note="R -> W (in SEMDSP; decreased function in double-
FT strand break repair via homologous recombination;
FT dbSNP:rs755575416)"
FT /evidence="ECO:0000269|PubMed:30773277,
FT ECO:0000269|PubMed:30773278"
FT /id="VAR_083022"
FT VARIANT 969..1378
FT /note="Missing (in SEMDSP)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083023"
FT VARIANT 973
FT /note="G -> R (in SEMDSP; decreased function in double-
FT strand break repair via homologous recombination;
FT dbSNP:rs1342198195)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083024"
FT VARIANT 1090
FT /note="L -> R (in SEMDSP; unknown pathological
FT significance; genomic instability; when associated with R-
FT 430)"
FT /evidence="ECO:0000269|PubMed:32959051"
FT /id="VAR_086304"
FT VARIANT 1197
FT /note="S -> P (in SEMDSP; dbSNP:rs1586681982)"
FT /evidence="ECO:0000269|PubMed:30773277"
FT /id="VAR_083025"
FT VARIANT 1276
FT /note="P -> L (in dbSNP:rs4925856)"
FT /id="VAR_042414"
FT VARIANT 1288
FT /note="E -> Q (in SEMDSP; unknown pathological
FT significance; dbSNP:rs1554878402)"
FT /evidence="ECO:0000269|PubMed:30773278"
FT /id="VAR_083026"
FT MUTAGEN 530
FT /note="E->A: Abolished interaction with histone H4 and
FT recruitment to replication forks without affecting
FT interaction with MMS22L."
FT /evidence="ECO:0000269|PubMed:27338793"
FT MUTAGEN 559
FT /note="D->A: Abolished interaction with histone H4 and
FT recruitment to replication forks without affecting
FT interaction with MMS22L."
FT /evidence="ECO:0000269|PubMed:27338793"
FT MUTAGEN 563
FT /note="W->A: Abolished interaction with histone H4 and
FT recruitment to replication forks without affecting
FT interaction with MMS22L."
FT /evidence="ECO:0000269|PubMed:27338793"
FT MUTAGEN 568
FT /note="E->A: Abolished interaction with histone H4 and
FT recruitment to replication forks without affecting
FT interaction with MMS22L."
FT /evidence="ECO:0000269|PubMed:27338793"
FT MUTAGEN 571
FT /note="N->A: Abolished interaction with histone H4 and
FT recruitment to replication forks without affecting
FT interaction with MMS22L."
FT /evidence="ECO:0000269|PubMed:27338793"
FT MUTAGEN 604
FT /note="D->A: Abolished interaction with histone H4 and
FT recruitment to replication forks without affecting
FT interaction with MMS22L."
FT /evidence="ECO:0000269|PubMed:27338793"
FT CONFLICT 193..194
FT /note="EQ -> DE (in Ref. 1; AAA85819)"
FT /evidence="ECO:0000305"
FT CONFLICT 268
FT /note="A -> R (in Ref. 1; AAA85819)"
FT /evidence="ECO:0000305"
FT CONFLICT 427
FT /note="P -> A (in Ref. 4; CAB63467)"
FT /evidence="ECO:0000305"
FT CONFLICT 482
FT /note="A -> R (in Ref. 1; AAA85819)"
FT /evidence="ECO:0000305"
FT CONFLICT 516
FT /note="R -> P (in Ref. 1; AAA85819)"
FT /evidence="ECO:0000305"
FT HELIX 532..539
FT /evidence="ECO:0007829|PDB:5JA4"
FT HELIX 542..551
FT /evidence="ECO:0007829|PDB:5JA4"
FT HELIX 565..572
FT /evidence="ECO:0007829|PDB:5JA4"
FT HELIX 575..583
FT /evidence="ECO:0007829|PDB:5JA4"
FT TURN 594..597
FT /evidence="ECO:0007829|PDB:5JA4"
FT HELIX 601..607
FT /evidence="ECO:0007829|PDB:5JA4"
FT HELIX 611..616
FT /evidence="ECO:0007829|PDB:5JA4"
FT HELIX 634..644
FT /evidence="ECO:0007829|PDB:5JA4"
FT HELIX 651..668
FT /evidence="ECO:0007829|PDB:5JA4"
SQ SEQUENCE 1378 AA; 150929 MW; 8E3013861864DCDE CRC64;
MSLERELRQL SKAKAKAQRA GQRREEAALC HQLGELLAGH GRYAEALEQH WQELQLRERA
DDPLGCAVAH RKIGERLAEM EDYPAALQHQ HQYLELAHSL RNHTELQRAW ATIGRTHLDI
YDHCQSRDAL LQAQAAFEKS LAIVDEELEG TLAQGELNEM RTRLYLNLGL TFESLQQTAL
CNDYFRKSIF LAEQNHLYED LFRARYNLGT IHWRAGQHSQ AMRCLEGARE CAHTMRKRFM
ESECCVVIAQ VLQDLGDFLA AKRALKKAYR LGSQKPVQRA AICQNLQHVL AVVRLQQQLE
EAEGRDPQGA MVICEQLGDL FSKAGDFPRA AEAYQKQLRF AELLDRPGAE RAIIHVSLAT
TLGDMKDHHG AVRHYEEELR LRSGNVLEEA KTWLNIALSR EEAGDAYELL APCFQKALSC
AQQAQRPQLQ RQVLQHLHTV QLRLQPQEAP ETETRLRELS VAEDEDEEEE AEEAAATAES
EALEAGEVEL SEGEDDTDGL TPQLEEDEEL QGHLGRRKGS KWNRRNDMGE TLLHRACIEG
QLRRVQDLVR QGHPLNPRDY CGWTPLHEAC NYGHLEIVRF LLDHGAAVDD PGGQGCEGIT
PLHDALNCGH FEVAELLLER GASVTLRTRK GLSPLETLQQ WVKLYRRDLD LETRQKARAM
EMLLQAAASG QDPHSSQAFH TPSSLLFDPE TSPPLSPCPE PPSNSTRLPE ASQAHVRVSP
GQAAPAMARP RRSRHGPASS SSSSEGEDSA GPARPSQKRP RCSATAQRVA AWTPGPASNR
EAATASTSRA AYQAAIRGVG SAQSRLGPGP PRGHSKALAP QAALIPEEEC LAGDWLELDM
PLTRSRRPRP RGTGDNRRPS STSGSDSEES RPRARAKQVR LTCMQSCSAP VNAGPSSLAS
EPPGSPSTPR VSEPSGDSSA AGQPLGPAPP PPIRVRVQVQ DHLFLIPVPH SSDTHSVAWL
AEQAAQRYYQ TCGLLPRLTL RKEGALLAPQ DLIPDVLQSN DEVLAEVTSW DLPPLTDRYR
RACQSLGQGE HQQVLQAVEL QGLGLSFSAC SLALDQAQLT PLLRALKLHT ALRELRLAGN
RLGDKCVAEL VAALGTMPSL ALLDLSSNHL GPEGLRQLAM GLPGQATLQS LEELDLSMNP
LGDGCGQSLA SLLHACPLLS TLRLQACGFG PSFFLSHQTA LGSAFQDAEH LKTLSLSYNA
LGAPALARTL QSLPAGTLLH LELSSVAAGK GDSDLMEPVF RYLAKEGCAL AHLTLSANHL
GDKAVRDLCR CLSLCPSLIS LDLSANPEIS CASLEELLST LQKRPQGLSF LGLSGCAVQG
PLGLGLWDKI AAQLRELQLC SRRLCAEDRD ALRQLQPSRP GPGECTLDHG SKLFFRRL
