ESPSearch: a program for finding exact sequences and patterns in DNA, RNA, or protein.

ESPSearch is a computer program for rapidly identifying nucleic acid or amino acid sequences of any length within any source sequence from promoters to entire genomes to protein libraries. ESPSearch utilizes a user-constructed database to identify many sequences simultaneously, including target sequences with wildcards and mismatches and user-specified patterns of those recognized sequences. Here we use ESPSearch to identify a variety of possible binding sites for dimeric artificial transcription factors within several p53 recognition sites and the promoter of the BAX gene. Heterodimeric and homodimeric proteins are designed using human zinc fingers by identifying groups of zinc finger binding sites meeting particular pattern constraints. ESPSearch is also used to estimate the specificity of each artificial transcription factor by searching the entire genome. Next, the specificity of several possible small interfering RNA (siRNA) sequences is determined by searching both the whole genome and the library of known human mRNAs. Finally, ESPSearch identifies proteins containing different forms of the LXXLL motif used in nuclear receptor-coactivator interactions from the human proteome, making use of user-defined groups of amino acids. ESPSearch could also be applied to other tasks involving sequence and pattern recognition on small and large scales. ESPSearch is freely available at http://web.chemistry.gatech.edu/-doyle/espsearch/.

[1]  Young Do Kwon,et al.  Human zinc fingers as building blocks in the construction of artificial transcription factors , 2003, Nature Biotechnology.

[2]  I. Longden,et al.  EMBOSS: the European Molecular Biology Open Software Suite. , 2000, Trends in genetics : TIG.

[3]  David S. Park,et al.  APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death , 2001, The Journal of cell biology.

[4]  David M. Heery,et al.  A signature motif in transcriptional co-activators mediates binding to nuclear receptors , 1997, Nature.

[5]  R. Juliano,et al.  Design of artificial transcription factors to selectively regulate the pro-apoptotic bax gene , 2002 .

[6]  Scot A Wolfe,et al.  Structure of a designed dimeric zinc finger protein bound to DNA. , 2003, Biochemistry.

[7]  M. Ptashne.  A Genetic Switch , 1986 .

[8]  Jeremy M Berg,et al.  The design of functional DNA-binding proteins based on zinc finger domains. , 2004, Chemical reviews.

[9]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[10]  Alexander E. Kel,et al.  TRANSFAC®: transcriptional regulation, from patterns to profiles , 2003, Nucleic Acids Res..

[11]  A. Schepartz,et al.  Effects of nucleic acids and polyanions on dimer formation and DNA binding by bZIP and bHLHZip transcription factors. , 2001, Bioorganic & medicinal chemistry.

[12]  Jonathan Pevsner,et al.  Basic Local Alignment Search Tool (BLAST) , 2005 .

[13]  D. Fowlkes,et al.  Dissection of the LXXLL Nuclear Receptor-Coactivator Interaction Motif Using Combinatorial Peptide Libraries: Discovery of Peptide Antagonists of Estrogen Receptors α and β , 1999, Molecular and Cellular Biology.

[14]  Amos Bairoch,et al.  The PROSITE database, its status in 2002 , 2002, Nucleic Acids Res..

[15]  Yusuke Nakamura,et al.  p53AIP1, a Potential Mediator of p53-Dependent Apoptosis, and Its Regulation by Ser-46-Phosphorylated p53 , 2000, Cell.

[16]  A. Schepartz,et al.  DNA specificity enhanced by sequential binding of protein monomers. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Mak,et al.  Regulation of PTEN transcription by p53. , 2001, Molecular cell.

[18]  Kristian Helin,et al.  APAF 1 is a key transcriptional target for p 53 in the regulation of neuronal cell death , 2001 .

[19]  John Calvin Reed,et al.  Tumor suppressor p53 is a direct transcriptional activator of the human bax gene , 1995, Cell.

[20]  Philippe Dessen,et al.  Further characterisation of the p53 responsive element – identification of new candidate genes for trans-activation by p53 , 1997, Oncogene.

[21]  Graziano Pesole,et al.  PatSearch: a program for the detection of patterns and structural motifs in nucleotide sequences , 2003, Nucleic Acids Res..

[22]  R. Beerli,et al.  Engineering polydactyl zinc-finger transcription factors , 2002, Nature Biotechnology.

[23]  Ola Snøve,et al.  Many commonly used siRNAs risk off-target activity. , 2004, Biochemical and biophysical research communications.