ID   SHLD2_HUMAN             Reviewed;         835 AA.
AC   Q86V20; O95885; Q9H991;
DT   22-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2003, sequence version 1.
DT   27-MAR-2024, entry version 154.
DE   RecName: Full=Shieldin complex subunit 2 {ECO:0000312|HGNC:HGNC:28773};
DE   AltName: Full=Protein FAM35A {ECO:0000305};
DE   AltName: Full=RINN1-REV7-interacting novel NHEJ regulator 2 {ECO:0000303|PubMed:29656893};
DE   AltName: Full=Shield complex subunit 2;
GN   Name=SHLD2 {ECO:0000303|PubMed:29656893, ECO:0000312|HGNC:HGNC:28773};
GN   Synonyms=FAM35A {ECO:0000312|HGNC:HGNC:28773}, RINN2
GN   {ECO:0000303|PubMed:29656893};
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] (ISOFORM 1).
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=15164054; DOI=10.1038/nature02462;
RA   Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA   Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA   Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA   Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA   Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA   Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA   Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA   Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA   Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA   Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA   Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA   Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA   McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA   Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA   Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA   Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA   Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA   Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA   Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA   Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA   Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 10.";
RL   Nature 429:375-381(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Eye;
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 [LARGE SCALE MRNA] OF 529-835 (ISOFORM 2).
RC   TISSUE=Brain;
RA   Mei G., Yu W., Gibbs R.A.;
RL   Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   FUNCTION, IDENTIFICATION IN THE SHIELDIN COMPLEX, INTERACTION WITH SHLD1;
RP   SHLD3 AND MAD2L2, SUBCELLULAR LOCATION, MUTAGENESIS OF 6-GLN--TRP-11, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=29656893; DOI=10.1016/j.cell.2018.03.050;
RA   Gupta R., Somyajit K., Narita T., Maskey E., Stanlie A., Kremer M.,
RA   Typas D., Lammers M., Mailand N., Nussenzweig A., Lukas J., Choudhary C.;
RT   "DNA repair network analysis reveals shieldin as a key regulator of NHEJ
RT   and PARP inhibitor sensitivity.";
RL   Cell 0:0-0(2018).
RN   [6]
RP   FUNCTION, INTERACTION WITH MAD2L2; TP53BP1 AND RIF1, SUBCELLULAR LOCATION,
RP   AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=29789392; DOI=10.15252/embj.201899543;
RA   Tomida J., Takata K.I., Bhetawal S., Person M.D., Chao H.P., Tang D.G.,
RA   Wood R.D.;
RT   "FAM35A associates with REV7 and modulates DNA damage responses of normal
RT   and BRCA1-defective cells.";
RL   EMBO J. 37:0-0(2018).
CC   -!- FUNCTION: Component of the shieldin complex, which plays an important
CC       role in repair of DNA double-stranded breaks (DSBs) (PubMed:29656893,
CC       PubMed:29789392). During G1 and S phase of the cell cycle, the complex
CC       functions downstream of TP53BP1 to promote non-homologous end joining
CC       (NHEJ) and suppress DNA end resection (PubMed:29656893,
CC       PubMed:29789392). Mediates various NHEJ-dependent processes including
CC       immunoglobulin class-switch recombination, and fusion of unprotected
CC       telomeres (PubMed:29656893). {ECO:0000269|PubMed:29656893,
CC       ECO:0000269|PubMed:29789392}.
CC   -!- SUBUNIT: Component of the shieldin complex, consisting of SHLD1, SHLD2,
CC       SHLD3 and MAD2L2/REV7 (PubMed:29656893, PubMed:29789392). Within the
CC       complex, SHLD2 forms a scaffold which interacts with a SHLD3-MAD2L2
CC       subcomplex via its N-terminus, and with SHLD1 via its C-terminus
CC       (PubMed:29656893). Interacts with TP53BP1 (PubMed:29789392). Interacts
CC       with RIF1 (PubMed:29789392). {ECO:0000269|PubMed:29656893,
CC       ECO:0000269|PubMed:29789392}.
CC   -!- INTERACTION:
CC       Q86V20; Q8IYI0: SHLD1; NbExp=2; IntAct=EBI-2560414, EBI-2560428;
CC       Q86V20-2; Q12888: TP53BP1; NbExp=3; IntAct=EBI-20592761, EBI-396540;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:29656893,
CC       ECO:0000269|PubMed:29789392}. Chromosome {ECO:0000269|PubMed:29656893,
CC       ECO:0000305|PubMed:29789392}. Note=Localizes to nuclear foci in
CC       response to DNA damage. {ECO:0000269|PubMed:29656893,
CC       ECO:0000269|PubMed:29789392}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q86V20-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q86V20-2; Sequence=VSP_016165;
CC   -!- MISCELLANEOUS: In BRCA1-deficient cells, function of the shieldin
CC       complex is necessary for sensitivity to camptothecin and the PARP
CC       inhibitor olaparib. {ECO:0000269|PubMed:29656893,
CC       ECO:0000269|PubMed:29789392}.
CC   -!- SIMILARITY: Belongs to the SHLD2 family. {ECO:0000305}.
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DR   EMBL; AK022978; BAB14342.1; -; mRNA.
DR   EMBL; AL645992; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC051863; AAH51863.1; -; mRNA.
DR   EMBL; AF131775; AAD20041.1; -; mRNA.
DR   CCDS; CCDS7383.1; -. [Q86V20-1]
DR   CCDS; CCDS81484.1; -. [Q86V20-2]
DR   RefSeq; NP_001317041.1; NM_001330112.1. [Q86V20-2]
DR   RefSeq; NP_061927.2; NM_019054.2. [Q86V20-1]
DR   PDB; 6KTO; X-ray; 3.45 A; D=1-52.
DR   PDB; 6WWA; X-ray; 3.80 A; X/Y=5-19.
DR   PDB; 7L9P; EM; 3.60 A; X/Y=5-19.
DR   PDBsum; 6KTO; -.
DR   PDBsum; 6WWA; -.
DR   PDBsum; 7L9P; -.
DR   AlphaFoldDB; Q86V20; -.
DR   SMR; Q86V20; -.
DR   BioGRID; 120024; 43.
DR   ComplexPortal; CPX-3481; Shieldin complex.
DR   CORUM; Q86V20; -.
DR   IntAct; Q86V20; 13.
DR   STRING; 9606.ENSP00000298786; -.
DR   iPTMnet; Q86V20; -.
DR   PhosphoSitePlus; Q86V20; -.
DR   BioMuta; FAM35A; -.
DR   DMDM; 74750445; -.
DR   EPD; Q86V20; -.
DR   jPOST; Q86V20; -.
DR   MassIVE; Q86V20; -.
DR   MaxQB; Q86V20; -.
DR   PaxDb; 9606-ENSP00000298784; -.
DR   PeptideAtlas; Q86V20; -.
DR   ProteomicsDB; 69948; -. [Q86V20-1]
DR   ProteomicsDB; 69949; -. [Q86V20-2]
DR   Antibodypedia; 45608; 95 antibodies from 18 providers.
DR   DNASU; 54537; -.
DR   Ensembl; ENST00000298784.5; ENSP00000298784.1; ENSG00000122376.12. [Q86V20-1]
DR   Ensembl; ENST00000298786.5; ENSP00000298786.3; ENSG00000122376.12. [Q86V20-2]
DR   GeneID; 54537; -.
DR   KEGG; hsa:54537; -.
DR   MANE-Select; ENST00000298786.5; ENSP00000298786.3; NM_001330112.2; NP_001317041.1. [Q86V20-2]
DR   UCSC; uc001kei.5; human. [Q86V20-1]
DR   AGR; HGNC:28773; -.
DR   CTD; 54537; -.
DR   DisGeNET; 54537; -.
DR   GeneCards; SHLD2; -.
DR   HGNC; HGNC:28773; SHLD2.
DR   HPA; ENSG00000122376; Low tissue specificity.
DR   MIM; 618029; gene.
DR   neXtProt; NX_Q86V20; -.
DR   OpenTargets; ENSG00000122376; -.
DR   PharmGKB; PA134926879; -.
DR   VEuPathDB; HostDB:ENSG00000122376; -.
DR   eggNOG; ENOG502QW94; Eukaryota.
DR   GeneTree; ENSGT00390000003133; -.
DR   HOGENOM; CLU_016120_0_0_1; -.
DR   InParanoid; Q86V20; -.
DR   OMA; TVHEDQW; -.
DR   OrthoDB; 2908579at2759; -.
DR   PhylomeDB; Q86V20; -.
DR   TreeFam; TF332107; -.
DR   PathwayCommons; Q86V20; -.
DR   SignaLink; Q86V20; -.
DR   BioGRID-ORCS; 54537; 108 hits in 1120 CRISPR screens.
DR   ChiTaRS; SHLD2; human.
DR   GenomeRNAi; 54537; -.
DR   Pharos; Q86V20; Tbio.
DR   PRO; PR:Q86V20; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; Q86V20; Protein.
DR   Bgee; ENSG00000122376; Expressed in calcaneal tendon and 106 other cell types or tissues.
DR   ExpressionAtlas; Q86V20; baseline and differential.
DR   GO; GO:0015629; C:actin cytoskeleton; IDA:HPA.
DR   GO; GO:0000785; C:chromatin; NAS:ComplexPortal.
DR   GO; GO:0005694; C:chromosome; IDA:UniProtKB.
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:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR   GO; GO:2000042; P:negative regulation of double-strand break repair via homologous recombination; IDA:UniProtKB.
DR   GO; GO:2001034; P:positive regulation of double-strand break repair via nonhomologous end joining; IDA:UniProtKB.
DR   GO; GO:0045830; P:positive regulation of isotype switching; IDA:UniProtKB.
DR   GO; GO:0010569; P:regulation of double-strand break repair via homologous recombination; IBA:GO_Central.
DR   GO; GO:0002208; P:somatic diversification of immunoglobulins involved in immune response; NAS:ComplexPortal.
DR   GO; GO:0043247; P:telomere maintenance in response to DNA damage; NAS:ComplexPortal.
DR   InterPro; IPR029715; FAM35A.
DR   InterPro; IPR031589; SHLD2_C.
DR   InterPro; IPR049507; SHLD2_OB1.
DR   PANTHER; PTHR14495; SHIELDIN COMPLEX SUBUNIT 2; 1.
DR   PANTHER; PTHR14495:SF2; SHIELDIN COMPLEX SUBUNIT 2; 1.
DR   Pfam; PF15793; SHLD2_C; 1.
DR   Pfam; PF21669; SHLD2_OB1; 1.
DR   Genevisible; Q86V20; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Chromosome; DNA damage; DNA repair;
KW   Nucleus; Reference proteome.
FT   CHAIN           1..835
FT                   /note="Shieldin complex subunit 2"
FT                   /id="PRO_0000087161"
FT   REGION          1..60
FT                   /note="Sufficient for interaction with SHLD3 and MAD2L2"
FT                   /evidence="ECO:0000269|PubMed:29656893"
FT   REGION          652..822
FT                   /note="Mediates interaction with SHLD1"
FT                   /evidence="ECO:0000269|PubMed:29656893"
FT   VAR_SEQ         654
FT                   /note="K -> KGYIWEFKYLFVQCNYTLENLELHTTPWSSCECLFDDDIRAITFKAK
FT                   FQKSAPSFVKISDLATHLEDKCS (in isoform 2)"
FT                   /evidence="ECO:0000303|Ref.4"
FT                   /id="VSP_016165"
FT   VARIANT         132
FT                   /note="F -> L (in dbSNP:rs3129520)"
FT                   /id="VAR_053997"
FT   VARIANT         550
FT                   /note="S -> C (in dbSNP:rs11202365)"
FT                   /id="VAR_053998"
FT   VARIANT         747
FT                   /note="R -> H (in dbSNP:rs11816168)"
FT                   /id="VAR_053999"
FT   MUTAGEN         6..11
FT                   /note="Missing: Fails to interact with SHLD3 or MAD2L2."
FT                   /evidence="ECO:0000269|PubMed:29656893"
FT   CONFLICT        529..532
FT                   /note="SQLL -> PRAI (in Ref. 4; AAD20041)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        723
FT                   /note="F -> L (in Ref. 1; BAB14342)"
FT                   /evidence="ECO:0000305"
FT   STRAND          37..43
FT                   /evidence="ECO:0007829|PDB:6KTO"
FT   STRAND          48..50
FT                   /evidence="ECO:0007829|PDB:6KTO"
SQ   SEQUENCE   835 AA;  93705 MW;  BD6D1D1E58C2605D CRC64;
     MSGGSQVHIF WGAPIAPLKI TVSEDTASLM SVADPWKKIQ LLYSQHSLYL KDEKQHKNLE
     NYKVPESIGS PDLSGHFLAN CMNRHVHVKD DFVRSVSETQ NIESQKIHSS RLSDITSSNM
     QICGFKSTVP HFTEEEKYQK LLSENKIRDE QPKHQPDICG KNFNTNLFQL GHKCAAVLDL
     VCSTEKINIG PEVVQRECVP TEYHEIQNQC LGLFSSNAVD KSRSEAAVRK VSDLKISTDT
     EFLSIITSSQ VAFLAQKKDK RRSPVNKGNV NMETEPKASY GEIRIPEENS IQLDGFTEAY
     ESGQNQAYSL ELFSPVCPKT ENSRIHINSD KGLEEHTGSQ ELFSSEDELP PNEIRIELCS
     SGILCSQLNT FHKSAIKRSC TSEDKVGQSE ALSRVLQVAK KMKLISNGGD SAVEMDRRNV
     SEFKSIKKTS LIKNCDSKSQ KYNCLVMVLS PCHVKEINIK FGPNSGSKVP LATVTVIDQS
     ETKKKVFLWR TAAFWAFTVF LGDIILLTDV VIHEDQWIGE TVLQSTFSSQ LLNLGSYSSI
     QPEEYSSVVS EVVLQDLLAY VSSKHSYLRD LPPRQPQRVN SIDFVELEHL QPDVLVHAVL
     RVVDFTILTE AVYSYRGQKQ KKVMLTVEQA QDQHYALVLW GPGAAWYPQL QRKKGVVLIK
     AQISELAFPI TASQKIALNA HSSLKSIFSS LPNIVYTGCA KCGLELETDE NRIYKQCFSC
     LPFTMKKIYY RPALMTAIDG RHDVCIRVES KLIEKILLNI SADCLNRVIV PSSEITYGMV
     VADLFHSLLA VSAEPCVLKI QSLFVLDENS YPLQQDFSLL DFYPDIVKHG ANARL
//