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 03-AUG-2022, entry version 142.
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}.
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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 AlphaFoldDB; P37573; -.
DR SMR; P37573; -.
DR STRING; 224308.BSU00880; -.
DR PaxDb; P37573; -.
DR PRIDE; P37573; -.
DR EnsemblBacteria; CAB11864; CAB11864; BSU_00880.
DR GeneID; 64301926; -.
DR GeneID; 936868; -.
DR KEGG; bsu:BSU00880; -.
DR PATRIC; fig|224308.179.peg.89; -.
DR eggNOG; COG1623; Bacteria.
DR InParanoid; P37573; -.
DR OMA; VVRDYVP; -.
DR PhylomeDB; P37573; -.
DR BioCyc; BSUB:BSU00880-MON; -.
DR BioCyc; MetaCyc:BSU00880-MON; -.
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:0106408; F:diadenylate cyclase activity; IEA:UniProtKB-EC.
DR GO; GO:0003677; F:DNA binding; 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; PF02457; DAC; 1.
DR Pfam; PF10635; DisA-linker; 1.
DR SUPFAM; SSF143597; SSF143597; 1.
DR SUPFAM; SSF47781; SSF47781; 1.
DR PROSITE; PS51794; DAC; 1.
PE 1: Evidence at protein level;
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 BINDING 78
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_01438"
FT BINDING 96
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_01438"
FT BINDING 109..113
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
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
