(data stored in ACNUC7421 zone)

SWISSPROT: DISA_BACSU

ID   DISA_BACSU              Reviewed;         360 AA.
AC   P37573;
DT   01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1994, sequence version 1.
DT   11-DEC-2019, entry version 131.
DE   RecName: Full=DNA integrity scanning protein DisA {ECO:0000255|HAMAP-Rule:MF_01438};
DE   AltName: Full=Cyclic di-AMP synthase {ECO:0000255|HAMAP-Rule:MF_01438};
DE            Short=c-di-AMP synthase {ECO:0000255|HAMAP-Rule:MF_01438};
DE   AltName: Full=Diadenylate cyclase {ECO:0000255|HAMAP-Rule:MF_01438};
DE            Short=DAC;
DE            EC=2.7.7.85 {ECO:0000255|HAMAP-Rule:MF_01438, ECO:0000269|PubMed:18439896};
GN   Name=disA {ECO:0000255|HAMAP-Rule:MF_01438};
GN   Synonyms=comY {ECO:0000303|PubMed:9141693},
GN   orf6 {ECO:0000303|PubMed:9141693}, yacK; OrderedLocusNames=BSU00880;
OS   Bacillus subtilis (strain 168).
OC   Bacteria; Firmicutes; Bacilli; Bacillales; Bacillaceae; Bacillus.
OX   NCBI_TaxID=224308;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=168;
RX   PubMed=7584024; DOI=10.1093/dnares/1.1.1;
RA   Ogasawara N., Nakai S., Yoshikawa H.;
RT   "Systematic sequencing of the 180 kilobase region of the Bacillus subtilis
RT   chromosome containing the replication origin.";
RL   DNA Res. 1:1-14(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=168;
RX   PubMed=9384377; DOI=10.1038/36786;
RA   Kunst F., Ogasawara N., Moszer I., Albertini A.M., Alloni G., Azevedo V.,
RA   Bertero M.G., Bessieres P., Bolotin A., Borchert S., Borriss R.,
RA   Boursier L., Brans A., Braun M., Brignell S.C., Bron S., Brouillet S.,
RA   Bruschi C.V., Caldwell B., Capuano V., Carter N.M., Choi S.-K.,
RA   Codani J.-J., Connerton I.F., Cummings N.J., Daniel R.A., Denizot F.,
RA   Devine K.M., Duesterhoeft A., Ehrlich S.D., Emmerson P.T., Entian K.-D.,
RA   Errington J., Fabret C., Ferrari E., Foulger D., Fritz C., Fujita M.,
RA   Fujita Y., Fuma S., Galizzi A., Galleron N., Ghim S.-Y., Glaser P.,
RA   Goffeau A., Golightly E.J., Grandi G., Guiseppi G., Guy B.J., Haga K.,
RA   Haiech J., Harwood C.R., Henaut A., Hilbert H., Holsappel S., Hosono S.,
RA   Hullo M.-F., Itaya M., Jones L.-M., Joris B., Karamata D., Kasahara Y.,
RA   Klaerr-Blanchard M., Klein C., Kobayashi Y., Koetter P., Koningstein G.,
RA   Krogh S., Kumano M., Kurita K., Lapidus A., Lardinois S., Lauber J.,
RA   Lazarevic V., Lee S.-M., Levine A., Liu H., Masuda S., Mauel C.,
RA   Medigue C., Medina N., Mellado R.P., Mizuno M., Moestl D., Nakai S.,
RA   Noback M., Noone D., O'Reilly M., Ogawa K., Ogiwara A., Oudega B.,
RA   Park S.-H., Parro V., Pohl T.M., Portetelle D., Porwollik S.,
RA   Prescott A.M., Presecan E., Pujic P., Purnelle B., Rapoport G., Rey M.,
RA   Reynolds S., Rieger M., Rivolta C., Rocha E., Roche B., Rose M., Sadaie Y.,
RA   Sato T., Scanlan E., Schleich S., Schroeter R., Scoffone F., Sekiguchi J.,
RA   Sekowska A., Seror S.J., Serror P., Shin B.-S., Soldo B., Sorokin A.,
RA   Tacconi E., Takagi T., Takahashi H., Takemaru K., Takeuchi M.,
RA   Tamakoshi A., Tanaka T., Terpstra P., Tognoni A., Tosato V., Uchiyama S.,
RA   Vandenbol M., Vannier F., Vassarotti A., Viari A., Wambutt R., Wedler E.,
RA   Wedler H., Weitzenegger T., Winters P., Wipat A., Yamamoto H., Yamane K.,
RA   Yasumoto K., Yata K., Yoshida K., Yoshikawa H.-F., Zumstein E.,
RA   Yoshikawa H., Danchin A.;
RT   "The complete genome sequence of the Gram-positive bacterium Bacillus
RT   subtilis.";
RL   Nature 390:249-256(1997).
RN   [3]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RC   STRAIN=168 / IS58;
RX   PubMed=9141693; DOI=10.1099/00221287-143-4-1309;
RA   Krueger E., Msadek T., Ohlmeier S., Hecker M.;
RT   "The Bacillus subtilis clpC operon encodes DNA repair and competence
RT   proteins.";
RL   Microbiology 143:1309-1316(1997).
RN   [4]
RP   FUNCTION, AND INDUCTION.
RC   STRAIN=168 / PY79;
RX   PubMed=16713562; DOI=10.1016/j.cell.2006.03.039;
RA   Bejerano-Sagie M., Oppenheimer-Shaanan Y., Berlatzky I., Rouvinski A.,
RA   Meyerovich M., Ben-Yehuda S.;
RT   "A checkpoint protein that scans the chromosome for damage at the start of
RT   sporulation in Bacillus subtilis.";
RL   Cell 125:679-690(2006).
RN   [5]
RP   INDUCTION.
RC   STRAIN=168 / 1604;
RX   PubMed=17434969; DOI=10.1128/jb.00130-07;
RA   Jervis A.J., Thackray P.D., Houston C.W., Horsburgh M.J., Moir A.;
RT   "SigM-responsive genes of Bacillus subtilis and their promoters.";
RL   J. Bacteriol. 189:4534-4538(2007).
RN   [6]
RP   FUNCTION, CATALYTIC ACTIVITY, COFACTOR, SUBSTRATE SPECIFICITY, ACTIVITY
RP   REGULATION, DNA-BINDING, SUBUNIT, AND MUTAGENESIS OF ASP-77 AND GLY-334.
RX   PubMed=18439896; DOI=10.1016/j.molcel.2008.02.020;
RA   Witte G., Hartung S., Buttner K., Hopfner K.P.;
RT   "Structural biochemistry of a bacterial checkpoint protein reveals
RT   diadenylate cyclase activity regulated by DNA recombination
RT   intermediates.";
RL   Mol. Cell 30:167-178(2008).
RN   [7]
RP   FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP   ASP-77.
RC   STRAIN=168 / PY79;
RX   PubMed=21566650; DOI=10.1038/embor.2011.77;
RA   Oppenheimer-Shaanan Y., Wexselblatt E., Katzhendler J., Yavin E.,
RA   Ben-Yehuda S.;
RT   "c-di-AMP reports DNA integrity during sporulation in Bacillus subtilis.";
RL   EMBO Rep. 12:594-601(2011).
RN   [8]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RC   STRAIN=168;
RX   PubMed=22211522; DOI=10.1111/j.1365-2958.2011.07953.x;
RA   Luo Y., Helmann J.D.;
RT   "Analysis of the role of Bacillus subtilis sigma(M) in beta-lactam
RT   resistance reveals an essential role for c-di-AMP in peptidoglycan
RT   homeostasis.";
RL   Mol. Microbiol. 83:623-639(2012).
RN   [9]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RC   STRAIN=168;
RX   PubMed=23192352; DOI=10.1074/jbc.m112.395491;
RA   Mehne F.M., Gunka K., Eilers H., Herzberg C., Kaever V., Stuelke J.;
RT   "Cyclic di-AMP homeostasis in Bacillus subtilis: both lack and high level
RT   accumulation of the nucleotide are detrimental for cell growth.";
RL   J. Biol. Chem. 288:2004-2017(2013).
RN   [10]
RP   INTERACTION WITH RADA.
RX   PubMed=23760274; DOI=10.1074/jbc.m113.464883;
RA   Zhang L., He Z.G.;
RT   "Radiation-sensitive gene A (RadA) targets DisA, DNA integrity scanning
RT   protein A, to negatively affect cyclic di-AMP synthesis activity in
RT   Mycobacterium smegmatis.";
RL   J. Biol. Chem. 288:22426-22436(2013).
RN   [11]
RP   FUNCTION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF ASP-77.
RC   STRAIN=168, 168 / PY79, and 168 / YB886 / BG214;
RX   PubMed=25616256; DOI=10.1016/j.dnarep.2014.12.007;
RA   Gandara C., Alonso J.C.;
RT   "DisA and c-di-AMP act at the intersection between DNA-damage response and
RT   stress homeostasis in exponentially growing Bacillus subtilis cells.";
RL   DNA Repair 27:1-8(2015).
RN   [12]
RP   FUNCTION.
RC   STRAIN=168;
RX   PubMed=26240071; DOI=10.1128/jb.00564-15;
RA   Gundlach J., Mehne F.M., Herzberg C., Kampf J., Valerius O., Kaever V.,
RA   Stuelke J.;
RT   "An essential poison: synthesis and degradation of cyclic di-AMP in
RT   Bacillus subtilis.";
RL   J. Bacteriol. 197:3265-3274(2015).
CC   -!- FUNCTION: Participates in a DNA-damage check-point that is active prior
CC       to asymmetric division when DNA is damaged (PubMed:9141693,
CC       PubMed:16713562). Forms globular foci that rapidly scan along the
CC       chromosomes during sporulation, searching for lesions. Its ability to
CC       scan through the chromosome rapidly is due to its non-specific DNA-
CC       binding. When a lesion is present, DisA pauses at the lesion site
CC       (PubMed:21566650). This triggers a cellular response that culminates in
CC       a temporary block in sporulation initiation. It is required, at least
CC       partially, to inhibit the activity of the transcription factor spo0A,
CC       which controls, among others, early sporulation genes. In B.subtilis c-
CC       di-AMP is a second messenger that mediates growth, DNA repair and cell
CC       wall homeostasis (PubMed:22211522); it is toxic when present in excess
CC       (PubMed:26240071). {ECO:0000269|PubMed:16713562,
CC       ECO:0000269|PubMed:21566650, ECO:0000269|PubMed:22211522,
CC       ECO:0000269|PubMed:26240071, ECO:0000269|PubMed:9141693}.
CC   -!- FUNCTION: One of 3 paralogous diadenylate cyclases (DAC) in this
CC       bacteria (PubMed:23192352). Has diadenylate cyclase activity,
CC       catalyzing the condensation of 2 ATP molecules into cyclic di-AMP (c-
CC       di-AMP) (PubMed:18439896, PubMed:25616256). c-di-AMP acts as a
CC       signaling molecule that couples DNA integrity with progression of
CC       sporulation. The rise in c-di-AMP level generated by DisA while
CC       scanning the chromosome operates as a positive signal that advances
CC       sporulation; upon encountering a lesion, the DisA focus arrests at the
CC       damaged site and halts c-di-AMP synthesis. Does not convert GTP to c-
CC       di-GMP (PubMed:18439896). {ECO:0000269|PubMed:18439896,
CC       ECO:0000269|PubMed:23192352, ECO:0000269|PubMed:25616256}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=2 ATP = 3',3'-c-di-AMP + 2 diphosphate; Xref=Rhea:RHEA:35655,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:71500; EC=2.7.7.85;
CC         Evidence={ECO:0000255|HAMAP-Rule:MF_01438,
CC         ECO:0000269|PubMed:18439896};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000255|HAMAP-Rule:MF_01438,
CC         ECO:0000269|PubMed:18439896};
CC   -!- ACTIVITY REGULATION: Diadenylate cyclase activity is inhibited by the
CC       interaction with RadA (By similarity). Diadenylate cyclase activity is
CC       not affected by ssDNA or dsDNA, but three- and four-way junctions
CC       strongly inhibit the activity of DisA, suggesting the enzyme is
CC       regulated by branched nucleic acids. {ECO:0000250|UniProtKB:A0R564,
CC       ECO:0000269|PubMed:18439896}.
CC   -!- SUBUNIT: Homooligomer (PubMed:18439896). Interacts with RadA
CC       (PubMed:23760274). {ECO:0000269|PubMed:18439896,
CC       ECO:0000269|PubMed:23760274}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21566650}.
CC       Note=Present in a puncate pattern at 1.5 hours after sporulation onset,
CC       does not co-localize with c-di-AMP phosphodiesterase GdpP.
CC       {ECO:0000269|PubMed:21566650}.
CC   -!- INDUCTION: Expression increases during late exponential phase and at
CC       the onset of sporulation (PubMed:16713562). Transcribed under partial
CC       control of SigM ECF sigma factor (PubMed:17434969).
CC       {ECO:0000269|PubMed:16713562, ECO:0000269|PubMed:17434969}.
CC   -!- DISRUPTION PHENOTYPE: Decreases c-di-AMP levels in mid-exponential
CC       phase from about 3.8 uM to about 2.8 uM in strain BG214
CC       (PubMed:25616256). No change in sensitivity to methyl methanesulfonate
CC       (MMS), decreased survival after UV irradiation in transition and
CC       stationary phase, strong decrease in competence (PubMed:9141693). Cells
CC       lacking this gene show a reduced c-di-AMP level compared to wild-type
CC       and cannot properly trigger the DNA damage response (PubMed:21566650).
CC       No effect on antibiotic sensitivity to the beta-lactam antibiotic
CC       cefuroxime (CEF), upon overexpression of the c-di-AMP phosphodiesterase
CC       GdpP increased sensitivity to CEF (PubMed:22211522). Double disA-cdaA
CC       mutants cannot be made, suggesting they are lethal, while double disA-
CC       cdaS and cdaA-cdaS mutants are viable (PubMed:22211522,
CC       PubMed:23192352). Depletion of cdaA in double disA-cdaA deletion cells
CC       leads to cell lysis (PubMed:22211522). Exponentially growing cells are
CC       100-fold more sensitive to MMS, no change in response to H(2)O(2) or
CC       nalidixic acid; a double disA-radA deletion suppresses H(2)O(2)
CC       sensitivity of the radA mutant, but has no effect on MMS sensitivity,
CC       suggesting radA and disA might work in the same DNA repair pathway
CC       (PubMed:25616256). {ECO:0000269|PubMed:21566650,
CC       ECO:0000269|PubMed:23192352, ECO:0000269|PubMed:25616256,
CC       ECO:0000269|PubMed:9141693}.
CC   -!- SIMILARITY: Belongs to the DisA family. {ECO:0000255|HAMAP-
CC       Rule:MF_01438}.
DR   EMBL; D26185; BAA05322.1; -; Genomic_DNA.
DR   EMBL; AL009126; CAB11864.1; -; Genomic_DNA.
DR   PIR; S66117; S66117.
DR   RefSeq; NP_387969.1; NC_000964.3.
DR   RefSeq; WP_003225736.1; NZ_JNCM01000029.1.
DR   SMR; P37573; -.
DR   STRING; 224308.BSU00880; -.
DR   PaxDb; P37573; -.
DR   PRIDE; P37573; -.
DR   EnsemblBacteria; CAB11864; CAB11864; BSU00880.
DR   GeneID; 936868; -.
DR   KEGG; bsu:BSU00880; -.
DR   PATRIC; fig|224308.179.peg.89; -.
DR   eggNOG; ENOG4105E59; Bacteria.
DR   eggNOG; COG1623; LUCA.
DR   HOGENOM; HOG000236713; -.
DR   InParanoid; P37573; -.
DR   KO; K07067; -.
DR   OMA; SKMDGAI; -.
DR   PhylomeDB; P37573; -.
DR   BioCyc; BSUB:BSU00880-MONOMER; -.
DR   BioCyc; MetaCyc:BSU00880-MONOMER; -.
DR   BRENDA; 2.7.7.85; 658.
DR   Proteomes; UP000001570; Chromosome.
DR   GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0004016; F:adenylate cyclase activity; IBA:GO_Central.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0003677; F:DNA binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0016779; F:nucleotidyltransferase activity; IEA:UniProtKB-UniRule.
DR   GO; GO:0006281; P:DNA repair; IEA:UniProtKB-UniRule.
DR   GO; GO:0019932; P:second-messenger-mediated signaling; IEA:UniProtKB-UniRule.
DR   Gene3D; 1.20.1260.110; -; 1.
DR   Gene3D; 3.40.1700.10; -; 1.
DR   HAMAP; MF_01438; DisA; 1.
DR   InterPro; IPR038331; DisA_sf.
DR   InterPro; IPR036888; DNA_integrity_DisA_N_sf.
DR   InterPro; IPR018906; DNA_integrity_scan_DisA_link.
DR   InterPro; IPR003390; DNA_integrity_scan_DisA_N.
DR   InterPro; IPR023763; DNA_integrity_scanning_protein.
DR   InterPro; IPR010994; RuvA_2-like.
DR   Pfam; PF10635; DisA-linker; 1.
DR   Pfam; PF02457; DisA_N; 1.
DR   SUPFAM; SSF143597; SSF143597; 1.
DR   SUPFAM; SSF47781; SSF47781; 1.
DR   PROSITE; PS51794; DAC; 1.
PE   1: Evidence at protein level;
DR   PRODOM; P37573.
DR   SWISS-2DPAGE; P37573.
KW   ATP-binding; Cytoplasm; DNA damage; DNA repair; DNA-binding; Magnesium;
KW   Nucleotide-binding; Nucleotidyltransferase; Reference proteome;
KW   Transferase.
FT   CHAIN           1..360
FT                   /note="DNA integrity scanning protein DisA"
FT                   /id="PRO_0000049450"
FT   DOMAIN          11..149
FT                   /note="DAC"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01130"
FT   NP_BIND         109..113
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_01438"
FT   BINDING         78
FT                   /note="ATP; via amide nitrogen"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_01438"
FT   BINDING         96
FT                   /note="ATP; via amide nitrogen and carbonyl oxygen"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_01438"
FT   MUTAGEN         77
FT                   /note="D->N: Loss of enzymatic activity. Fails to form the
FT                   normal DisA focus. Cannot trigger the DNA damage response.
FT                   Increased sensitivity to methyl methanesulfonate."
FT                   /evidence="ECO:0000269|PubMed:18439896,
FT                   ECO:0000269|PubMed:21566650, ECO:0000269|PubMed:25616256"
FT   MUTAGEN         334
FT                   /note="G->E: Reduction in the capability of the four-way
FT                   junction DNA to inhibit diadenylate cyclase. Reduction in
FT                   DNA-binding."
FT                   /evidence="ECO:0000269|PubMed:18439896"
SQ   SEQUENCE   360 AA;  40734 MW;  92994B4A916026A9 CRC64;
     MEKEKKGAKH ELDLSSILQF VAPGTPLRAG MENVLRANTG GLIVVGYNDK VKEVVDGGFH
     INTAFSPAHL YELAKMDGAI ILSDSGQKIL YANTQLMPDA TISSSETGMR HRTAERVAKQ
     TGCLVIAISE RRNVITLYQE NMKYTLKDIG FILTKANQAI QTLEKYKTIL DKTINALNAL
     EFEELVTFSD VLSVMHRYEM VLRIKNEINM YIKELGTEGH LIKLQVIELI TDMEEEAALF
     IKDYVKEKIK DPFVLLKELQ DMSSYDLLDD SIVYKLLGYP ASTNLDDYVL PRGYRLLNKI
     PRLPMPIVEN VVEAFGVLPR IIEASAEELD EVEGIGEVRA QKIKKGLKRL QEKHYLDRQL
//

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