RegulonDB RegulonDB 11.1: Gene Form

rrsD gene in Escherichia coli K-12 genome

Gene local context to scale (view description)

rrsD yrdA ileU yrdB Fis Fis Fis Fis Fis DksA DksA DksA-ppGpp DksA-ppGpp DksA-ppGpp DksA-ppGpp ppGpp ppGpp TSS_3601 TSS_3601 rrsDp1 rrsDp1 rrsDp rrsDp rrsDp2 rrsDp2 TSS_3600 TSS_3600

Name: rrsD    Texpresso search in the literature
Synonym(s): ECK3265, EG30087, b3278
Genome position(nucleotides): 3427221 <-- 3428762
Strand: reverse
Sequence: Get nucleotide sequence FastaFormat
GC content %:  
External database links:  

Name: 16S ribosomal RNA
Synonym(s): 16S rRNA, rrsD, rrsD 16S ribosomal RNA
Type: rRNA
Cellular location: cytosol
Multifun Terms (GenProtEC)  
  2 - information transfer --> 2.2 - RNA related --> 2.2.6 - rRNA, stable RNA
  2 - information transfer --> 2.3 - protein related --> 2.3.2 - translation
  6 - cell structure --> 6.6 - ribosomes
Gene Ontology Terms (GO)  
cellular_component GO:0005737 - cytoplasm
GO:0022627 - cytosolic small ribosomal subunit
biological_process GO:0006412 - translation
Note(s): Note(s): ...[more].
Reference(s): [1] Afonina EI., et al., 1991
[2] Aksoy S., et al., 1984
[3] Amarantos I., et al., 2002
[4] Behrens S., et al., 2003
[5] Berg KL., et al., 1987
[6] Bessarab DA., et al., 1998
[7] Bogdanova SL., et al., 1995
[8] Bremer H., et al., 1971
[9] Budker VG., et al., 1980
[10] Cangelosi GA., et al., 1997
[11] Chaney SG., et al., 1977
[12] Csordas-Toth E., et al., 1979
[13] Dennis PP., et al., 1976
[14] Draper DE., et al., 1988
[15] Fox JW., et al., 1978
[16] Friedrich K., et al., 1988
[17] Fuchs BM., et al., 2000
[18] Glaser G., et al., 1977
[19] Gorelic L. 1976
[20] Gustafsson C., et al., 1993
[21] Harvey S., et al., 1990
[22] Harvey S., et al., 1988
[23] Heinrich T., et al., 1995
[24] Hill WE., et al., 1977
[25] Horie K., et al., 1983
[26] Hraiky C., et al., 2000
[27] Igarashi K., et al., 1977
[28] Kliber JS., et al., 1976
[29] Kossman CR., et al., 1971
[30] Krynetskii EIu., et al., 1979
[31] Lasater LS., et al., 1989
[32] Lewicki BT., et al., 1993
[33] Lindahl L., et al., 1975
[34] Lund E., et al., 1976
[35] Mahara A., et al., 2003
[36] Matsubara M., et al., 1972
[37] Mawn MV., et al., 2002
[38] Miller DR., et al., 1976
[39] Mohanty BK., et al., 2000
[40] Morgan EA., et al., 1978
[41] Morgan EA., et al., 1977
[42] Mori H., et al., 1990
[43] Morris DR., et al., 1975
[44] Muralikrishna P., et al., 1994
[45] Muto A. 1975
[46] Muto A. 1977
[47] Muto A. 1977
[48] Nisen P., et al., null
[49] Noller HF., et al., 1972
[50] Orosz A., et al., 1991
[51] Palmer ML., et al., 1979
[52] Pardon B., et al., 1994
[53] Pfeiffer T., et al., 1997
[54] Philippe C., et al., 1994
[55] Polacek N., et al., 1998
[56] Reiness G., et al., 1975
[57] Shen WF., et al., 1982
[58] Shimada N., et al., 2002
[59] Siehnel RJ., et al., 1985
[60] Sigmund CD., et al., 1982
[61] Srivastava AK., et al., 1991
[62] Steen R., et al., 1986
[63] Sykes J., et al., 1977
[64] Szymkowiak C., et al., 1987
[65] Theissen G., et al., 1993
[66] Vola C., et al., 1977
[67] Vollenweider HJ., et al., 1978
[68] Yamagishi M., et al., 1987
[69] Yamamoto M., et al., 1976
[70] Young RA., et al., 1979
[71] Yu MT., et al., 1970
[72] Zacharias M., et al., 1991
[73] Zacharias M., et al., 1989
[74] Zacharias M., et al., 1987
[75] Zenkova MA., et al., 1990
[76] Zenkova MA., et al., null
[77] Zenkova MA., et al., 1989
[78] Zenkova MA., et al., 1991
[79] Zenkova MA., et al., 1990
[80] de Boer HA., et al., 1979
[81] van Knippenberg PH., et al., 1988
External database links:  

Name: rrsD-ileU-alaU-rrlD-rrfD-thrV-rrfF         
Operon arrangement:
Transcription unit        Promoter

Transcriptional Regulation      
Display Regulation             
Activated by: Fis
Repressed by: H-NS, Lrp

Elements in the selected gene context region unrelated to any object in RegulonDB      

  Type Name Post Left Post Right Strand Notes Evidence (Confirmed, Strong, Weak) References
  promoter TSS_3600 3428877 reverse nd [RS-EPT-CBR] [82]
  promoter TSS_3601 3429211 forward nd [RS-EPT-CBR] [82]


 [RS-EPT-CBR] RNA-seq using two enrichment strategies for primary transcripts and consistent biological replicates


 [1] Afonina EI., Chichkova NV., Bogdanov AA., 1991, RNA-RNA and RNA-protein interactions in 30 S ribosomal subunits. Association of 16 S rRNA fragments in the presence of ribosomal proteins., FEBS Lett 283(2):251-4

 [2] Aksoy S., Squires CL., Squires C., 1984, Evidence for antitermination in Escherichia coli RRNA transcription., J Bacteriol 159(1):260-4

 [3] Amarantos I., Zarkadis IK., Kalpaxis DL., 2002, The identification of spermine binding sites in 16S rRNA allows interpretation of the spermine effect on ribosomal 30S subunit functions., Nucleic Acids Res 30(13):2832-43

 [4] Behrens S., Fuchs BM., Mueller F., Amann R., 2003, Is the in situ accessibility of the 16S rRNA of Escherichia coli for Cy3-labeled oligonucleotide probes predicted by a three-dimensional structure model of the 30S ribosomal subunit?, Appl Environ Microbiol 69(8):4935-41

 [5] Berg KL., Squires CL., Squires C., 1987, In vivo translation of a region within the rrnB 16S rRNA gene of Escherichia coli., J Bacteriol 169(4):1691-701

 [6] Bessarab DA., Kaberdin VR., Wei CL., Liou GG., Lin-Chao S., 1998, RNA components of Escherichia coli degradosome: evidence for rRNA decay., Proc Natl Acad Sci U S A 95(6):3157-61

 [7] Bogdanova SL., Degtiarev AI., Baranov PV., Dokudovskaia SS., Lavrik IN., Dontsova OA., Oretskaia TS., Krynetskaia IF., Shabarova ZA., Bogdanov AA., 1995, [Directed cleavage of the 16S rRNA molecule at a single internucleotide bond], Biokhimiia 60(2):297-307

 [8] Bremer H., Berry L., 1971, Co-transcription of 16S and 23S ribosomal RNA in Escherichia coli., Nat New Biol 234(46):81-3

 [9] Budker VG., Kobets ND., Kollektsionok IE., Karpova GG., Grineva NI., 1980, [Affinity labeling of ribosomes from Escherichia coli with 4-(N-2-chloroethyl, N-methylamino)-benzaldehyde actyl derivatives of oligouridylates]., Mol Biol (Mosk) 14(3):507-16

 [10] Cangelosi GA., Brabant WH., 1997, Depletion of pre-16S rRNA in starved Escherichia coli cells., J Bacteriol 179(14):4457-63

 [11] Chaney SG., Jackson JM., Harris JS., 1977, A new mutation affecting ribosomal RNA synthesis in Escherichia coli., Biochemistry 16(16):3603-7

 [12] Csordas-Toth E., Boros I., Venetianer P., 1979, Structure of the promoter region for the rrnB gene in Escherichia coli., Nucleic Acids Res 7(8):2189-97

 [13] Dennis PP., Nordan DH., 1976, Characterization of the hybridization between purified 16S and 23S ribosomal ribonucleic acid and ribosomal deoxyribonucleic acid from Escherichia coli., J Bacteriol 128(1):28-34

 [14] Draper DE., White SA., Kean JM., 1988, Preparation of specific ribosomal RNA fragments., Methods Enzymol 164:221-37

 [15] Fox JW., Owens DP., Wong KP., 1978, Structural changes of ribosome by the action of ethylene glycol., Biochemistry 17(8):1357-64

 [16] Friedrich K., Woolley P., 1988, Electrostatic potential of macromolecules measured by pKa shift of a fluorophore. 1. The 3' terminus of 16S RNA., Eur J Biochem 173(1):227-31

 [17] Fuchs BM., Glockner FO., Wulf J., Amann R., 2000, Unlabeled helper oligonucleotides increase the in situ accessibility to 16S rRNA of fluorescently labeled oligonucleotide probes., Appl Environ Microbiol 66(8):3603-7

 [18] Glaser G., Enquist L., Cashel M., 1977, ColE1 cloning of a ribosomal RNA promoter region from lambdarifd18 by selection for lambda integration and excision functions., Gene 2(3-4):159-72

 [19] Gorelic L., 1976, Demonstration of ribosome-dependent photoinduced chain breakage of the 16S ribosomal ribonucleic acid component of the Escherichia coli 30S ribosomal subunit., Biochemistry 15(25):5474-80

 [20] Gustafsson C., Bjork GR., 1993, The tRNA-(m5U54)-methyltransferase of Escherichia coli is present in two forms in vivo, one of which is present as bound to tRNA and to a 3'-end fragment of 16 S rRNA., J Biol Chem 268(2):1326-31

 [21] Harvey S., Hill CW., 1990, Exchange of spacer regions between rRNA operons in Escherichia coli., Genetics 125(4):683-90

 [22] Harvey S., Hill CW., Squires C., Squires CL., 1988, Loss of the spacer loop sequence from the rrnB operon in the Escherichia coli K-12 subline that bears the relA1 mutation., J Bacteriol 170(3):1235-8

 [23] Heinrich T., Condon C., Pfeiffer T., Hartmann RK., 1995, Point mutations in the leader boxA of a plasmid-encoded Escherichia coli rrnB operon cause defective antitermination in vivo., J Bacteriol 177(13):3793-800

 [24] Hill WE., Bakke KR., Blair DP., 1977, On the sedimentation behavior and molecular weight of 16S ribosomal RNA from Escherichia coli., Nucleic Acids Res 4(2):473-6

 [25] Horie K., Hagihara H., Wada A., Fukutome H., 1983, Magnesium ion induced proton release as a probe for the polyelectrolytic structure of ribosomal RNAs and subunits., J Biochem (Tokyo) 94(4):1289-99

 [26] Hraiky C., Raymond MA., Drolet M., 2000, RNase H overproduction corrects a defect at the level of transcription elongation during rRNA synthesis in the absence of DNA topoisomerase I in Escherichia coli., J Biol Chem 275(15):11257-63

 [27] Igarashi K., Watanabe Y., Matsumoto E., Kogo A., Yabuki M., 1977, Responsibility of 16S RNA for the stimulation of polypeptide synthesis by spermidine., Biochem Biophys Res Commun 76(1):18-25

 [28] Kliber JS., Hoa GH., Douzou P., Graffe M., Grunberg-Manago M., 1976, Implications of electrostatic potentials on ribosomal proteins., Nucleic Acids Res 3(12):3423-38

 [29] Kossman CR., Stamato TD., Pettijohn DE., 1971, Tandem synthesis of the 16S and 23S ribosomal RNA sequences of Escherichia coli., Nat New Biol 234(47):102-4

 [30] Krynetskii EIu., Ivanovskaia MG., Drutsa VL., Purmal' AA., Sokolova NI., 1979, [Synthesis of photoaffinity reagents octadesoxyribonucleotide derived of the complementary portion of the 3'-terminal fragment of 16S rRNA of Escherichia coli ribosomes], Dokl Akad Nauk SSSR 247(3):752-4

 [31] Lasater LS., Cann PA., Glitz DG., 1989, Localization of the site of cleavage of ribosomal RNA by colicin E3. Placement on the small ribosomal subunit by electron microscopy of antibody--complementary oligodeoxynucleotide complexes., J Biol Chem 264(36):21798-805

 [32] Lewicki BT., Margus T., Remme J., Nierhaus KH., 1993, Coupling of rRNA transcription and ribosomal assembly in vivo. Formation of active ribosomal subunits in Escherichia coli requires transcription of rRNA genes by host RNA polymerase which cannot be replaced by bacteriophage T7 RNA polymerase., J Mol Biol 231(3):581-93

 [33] Lindahl L., Jaskunas SR., Dennis PP., Nomura M., 1975, Cluster of genes in Escherichia coli for ribosomal proteins, ribosomal RNA, and RNA polymerase subunits., Proc Natl Acad Sci U S A 72(7):2743-7

 [34] Lund E., Dahlberg JE., Lindahl L., Jaskunas SR., Dennis PP., Nomura M., 1976, Transfer RNA genes between 16S and 23S rRNA genes in rRNA transcription units of E. coli., Cell 7(2):165-77

 [35] Mahara A., Sakamoto T., Munaka T., Iwase R., Yamaoka T., Murakami A., 2003, Detection of acceptor sites for antisense oligonucleotides on native folded RNA by fluorescence-labeled oligonucleotide., Nucleic Acids Res Suppl (3):73-4

 [36] Matsubara M., Takata R., Osawa S., 1972, Chromosomal loci for 16S ribosomal RNA in Escherichia coli., Mol Gen Genet 117(4):311-7

 [37] Mawn MV., Fournier MJ., Tirrell DA., Mason TL., 2002, Depletion of free 30S ribosomal subunits in Escherichia coli by expression of RNA containing Shine-Dalgarno-like sequences., J Bacteriol 184(2):494-502

 [38] Miller DR., Matheson AT., Visentin LP., 1976, Ribosomal RNA: the message or matrix for ribosomal proteins., Can J Biochem 54(2):192-3

 [39] Mohanty BK., Kushner SR., 2000, Polynucleotide phosphorylase, RNase II and RNase E play different roles in the in vivo modulation of polyadenylation in Escherichia coli., Mol Microbiol 36(4):982-94

 [40] Morgan EA., Ikemura T., Lindahl L., Fallon AM., Nomura M., 1978, Some rRNA operons in E. coli have tRNA genes at their distal ends., Cell 13(2):335-44

 [41] Morgan EA., Ikemura T., Nomura M., 1977, Identification of spacer tRNA genes in individual ribosomal RNA transcription units of Escherichia coli., Proc Natl Acad Sci U S A 74(7):2710-4

 [42] Mori H., Dammel C., Becker E., Triman K., Noller HF., 1990, Single base alterations upstream of the E. coli 16S rRNA coding region result in temperature-sensitive 16S rRNA expression., Biochim Biophys Acta 1050(1-3):323-7

 [43] Morris DR., Dahlberg JE., Dahlberg AE., 1975, Detection of cation-specific conformational changes in ribosomal RNA by gel electrophoresis., Nucleic Acids Res 2(4):447-58

 [44] Muralikrishna P., Cooperman BS., 1994, A photolabile oligodeoxyribonucleotide probe of the decoding site in the small subunit of the Escherichia coli ribosome: identification of neighboring ribosomal components., Biochemistry 33(6):1392-8

 [45] Muto A., 1975, Preferential ribosomal RNA synthesis in the lysate of Escherichia coli., Mol Gen Genet 138(1):1-10

 [46] Muto A., 1977, Control of ribosomal RNA synthesis in Escherichia coli. II. Ribosomal RNA synthesis in isolated nucleoids., Mol Gen Genet 152(3):153-9

 [47] Muto A., 1977, Control of ribosomal RNA synthesis in Escherichia coli. III. Cytoplasmic factors for ribosomal RNA synthesis., Mol Gen Genet 152(3):161-5

 [48] Nisen P., Shapiro L., null, E. coli ribosomal RNA contains sequences homologous to insertion sequences IS1 and IS2., Nature 282(5741):872-4

 [49] Noller HF., Chaires JB., 1972, Functional modification of 16S ribosomal RNA by kethoxal., Proc Natl Acad Sci U S A 69(11):3115-8

 [50] Orosz A., Boros I., Venetianer P., 1991, Analysis of the complex transcription termination region of the Escherichia coli rrnB gene., Eur J Biochem 201(3):653-9

 [51] Palmer ML., Raker MA., Kennedy PJ., Young JW., Barnes WM., Rodriguez RL., Noller HF., 1979, Isolation and restriction mapping of plasmids containing ribosomal DNA sequences from the rrn B cistron of E. coli., Mol Gen Genet 172(2):171-8

 [52] Pardon B., Thelen L., Wagner R., 1994, The Escherichia coli ribosomal RNA leader: a structural and functional investigation., Biol Chem Hoppe Seyler 375(1):11-20

 [53] Pfeiffer T., Hartmann RK., 1997, Role of the spacer boxA of Escherichia coli ribosomal RNA operons in efficient 23 S rRNA synthesis in vivo., J Mol Biol 265(4):385-93

 [54] Philippe C., Benard L., Eyermann F., Cachia C., Kirillov SV., Portier C., Ehresmann B., Ehresmann C., 1994, Structural elements of rps0 mRNA involved in the modulation of translational initiation and regulation of E. coli ribosomal protein S15., Nucleic Acids Res 22(13):2538-46

 [55] Polacek N., Barta A., 1998, Metal ion probing of rRNAs: evidence for evolutionarily conserved divalent cation binding pockets., RNA 4(10):1282-94

 [56] Reiness G., Yang HL., Zubay G., Cashel M., 1975, Effects of guanosine tetraphosphate on cell-free synthesis of Escherichia coli ribosomal RNA and other gene products., Proc Natl Acad Sci U S A 72(8):2881-5

 [57] Shen WF., Squires C., Squires CL., 1982, Nucleotide sequence of the rrnG ribosomal RNA promoter region of Escherichia coli., Nucleic Acids Res 10(10):3303-13

 [58] Shimada N., Oniwa K., Iwase R., Yamaoka T., Murakami A., 2002, Selection of RNA-binding peptides containing Arg-rich motif., Nucleic Acids Res Suppl (2):281-2

 [59] Siehnel RJ., Morgan EA., 1985, Unbalanced rRNA gene dosage and its effects on rRNA and ribosomal-protein synthesis., J Bacteriol 163(2):476-86

 [60] Sigmund CD., Morgan EA., 1982, Erythromycin resistance due to a mutation in a ribosomal RNA operon of Escherichia coli., Proc Natl Acad Sci U S A 79(18):5602-6

 [61] Srivastava AK., Schlessinger D., 1991, Structure and organization of ribosomal DNA., Biochimie 73(6):631-8

 [62] Steen R., Dahlberg AE., Lade BN., Studier FW., Dunn JJ., 1986, T7 RNA polymerase directed expression of the Escherichia coli rrnB operon., EMBO J 5(5):1099-103

 [63] Sykes J., Metcalf E., Pickering JD., 1977, The nature of the proteins in 'chloramphenicol particles' from Escherichia coli A19 (Hfr rel met rns)., J Gen Microbiol 98(1):1-16

 [64] Szymkowiak C., Wagner R., 1987, Effects of deletions in the spacer region of the rrnB operon on the transcription of the large ribosomal RNAs from Escherichia coli., Mol Microbiol 1(3):327-34

 [65] Theissen G., Thelen L., Wagner R., 1993, Some base substitutions in the leader of an Escherichia coli ribosomal RNA operon affect the structure and function of ribosomes. Evidence for a transient scaffold function of the rRNA leader., J Mol Biol 233(2):203-18

 [66] Vola C., Jarry B., Rosset R., 1977, Linkage of 5S RNA and 16S+23S RNA genes on the E. coli chromosome., Mol Gen Genet 153(3):337-41

 [67] Vollenweider HJ., Stettler U., Kubler O., Koller T., Weber H., 1978, Refined molecular weights for phage, viral and ribosomal RNA., Gene 3(4):353-7

 [68] Yamagishi M., de Boer HA., Nomura M., 1987, Feedback regulation of rRNA synthesis. A mutational alteration in the anti-Shine-Dalgarno region of the 16 S rRNA gene abolishes regulation., J Mol Biol 198(3):547-50

 [69] Yamamoto M., Lindahl L., Nomura M., 1976, Synthesis of ribosomal RNA in E. coli: analysis using deletion mutants of a lambda transducing phage carrying ribosomal RNA genes., Cell 7(2):179-90

 [70] Young RA., Steitz JA., 1979, Tandem promoters direct E. coli ribosomal RNA synthesis., Cell 17(1):225-34

 [71] Yu MT., Vermeulen CW., Atwood KC., 1970, Location of the genes for 16S and 23S ribosomal RNA in the genetic map of Escherichia coli., Proc Natl Acad Sci U S A 67(1):26-31

 [72] Zacharias M., Theissen G., Bradaczek C., Wagner R., 1991, Analysis of sequence elements important for the synthesis and control of ribosomal RNA in E coli., Biochimie 73(6):699-712

 [73] Zacharias M., Wagner R., 1989, Functional characterization of a putative internal promoter sequence between the 16S and the 23S RNA genes within the Escherichia coli rrnB operon., Mol Microbiol 3(3):405-10

 [74] Zacharias M., Wagner R., 1987, Deletions in the tL structure upstream to the rRNA genes in the E. coli rrnB operon cause transcription polarity., Nucleic Acids Res 15(20):8235-48

 [75] Zenkova MA., Fedorova OS., Levina AS., Mamaev SV., Karpova GG., 1990, The influence of oligonucleotide-effector on the selectivity of sequence specific modification of 16 S rRNA., FEBS Lett 269(1):26-8

 [76] Zenkova MA., Karpova GG., Levina AS., null, [Complementary addressed alkylation of Escherichia coli 16S rRNA with 2',3'-O-[4-2-chloroethyl)-N-methylamino]benzylidene derivatives of deoxyribooligonucleotides. II. The nature of rapid interaction at 0 degrees C], Mol Biol (Mosk) 21(4):1130-6

 [77] Zenkova MA., Karpova GG., Levina AS., 1989, [Complementary addressed alkylation of 16s rRNA from Escherichia coli by 2',3'-0-[4-N-(2-chloroethyl)-N-methylamino]benzylidene derivatives of oligodeoxyribonucleotides. III. Segments of 16s rRNA interacting with the benzylidene derivative of d(pACCTTGTT)rA]., Mol Biol (Mosk) 23(4):1057-66

 [78] Zenkova MA., Karpova GG., Levina AS., Mamaev SV., Pazarova IuN., Fedorova OS., 1991, [Complementary addressed alkylation of 16S rRNA of Escherichia coli by 2',3'-O-[4-N-methyl-N-(2-chloroethyl)-amino]benzylidene derivatives of oligodeoxyribonucleotides. V. Study of the factors affecting selectivity of modification], Bioorg Khim 17(4):470-81

 [79] Zenkova MA., Karpova GG., Levina AS., Mamaev SV., Solov'ev VV., 1990, [Complementary addressed alkylation of Escherichia coli 16S rRNA with 2',3'-O-[4-N-methyl-N-(2-chloroethyl)aminobenzylidene]m derivatives of oligodeoxyribonucleotides. IV. Determination of binding sites of 16S rRNA with benzylidene derivatives of d(pACCTTGTT)rA, d(pTTACGACT)rU, d(TTTGCTCCCC)rA], Bioorg Khim 16(6):788-800

 [80] de Boer HA., Gilbert SF., Nomura M., 1979, DNA sequences of promoter regions for rRNA operons rrnE and rrnA in E. coli., Cell 17(1):201-9

 [81] van Knippenberg PH., Heus HA., 1988, Isolation and characterization of colicin fragments of bacterial 16S ribosomal RNA., Methods Enzymol 164:188-200

 [82] Salgado H, Peralta-Gil M, Gama-Castro S, Santos-Zavaleta A, Muñiz-Rascado L, García-Sotelo JS, Weiss V, Solano-Lira H, Martínez-Flores I, Medina-Rivera A, Salgado-Osorio G, Alquicira-Hernández S, Alquicira-Hernández K, López-Fuentes A, Porrón-Sotelo L, Huerta AM, Bonavides-Martínez C, Balderas-Martínez YI, Pannier L, Olvera M, Labastida A, Jiménez-Jacinto V, Vega-Alvarado L, Del Moral-Chávez V, Hernández-Alvarez A, Morett E, Collado-Vides J., 2012, RegulonDB v8.0: omics data sets, evolutionary conservation, regulatory phrases, cross-validated gold standards and more., Nucleic Acids Res.