University of Medicine and Dentistry of New Jersey

Aiello, D., Barnes, M. H., Biswas, E. E., Biswas, S. B., Gu, S., Williams, J. D., Bowlin, T. L., and Moir, D. T. Discovery, characterization and comparison of inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicases.. Bioorganic & Medicinal Chemistry. Vol. 17: 4466-4476 (2009 July ) , Publication ID: 19477652 .

Subhasis B. Biswas, Eric Wydra, Esther E. Biswas Novel Mechanism of DNA Binding and Regulation of Bacillus anthracis DNA Primase . Biochemistry. Vol. 00: In Press (2009 September ) , Publication ID: 19583259 .

Biswas, S.B.*, Clark, J.C., Kurpad, D.S., & Biswas, E.E. Bacterial Replicative DNA Helicases: A Review. in Bacterial DNA, DNA Polymerases, & DNA Helicases. Vol. Eds.: Walter D. Knudsen and Sam S. Bruns: In Press. (2009 November ) Click Here for more information. .

Biswas, E. E., Barnes, M., Moir, D. T., and Biswas, S. B. An Essential DnaB Helicase from Bacillus anthracis: Identification, Expression, and Charaterization.. Journal of Bacteriology. Vol. 191: 249-260 (2009 January ) , Publication ID: 18931108 .

Biswas S. B., Biswas-Fiss E. E. Quantitative analysis of binding of single-stranded DNA by Escherichia coli DnaB helicase and the DnaB x DnaC complex.. Biochemistry. Vol. 45: 11505-11513 (2006 ) , Publication ID: 16981710 .

Mitkova AV, Biswas-Fiss EE, Biswas S Modulation of DNA synthesis in Saccharomyces cerevisiae nuclear extract by DNA polymerases and the origin recognition complex. J Biol Chem. Vol. Feb 25 2005;280(8): 6285-6292 (2005 ) , Publication ID: 15590683 .

Biswas S, Khopde SM, Biswas-Fiss EE Control of ATP-dependent binding of Saccharomyces cerevisiae origin recognition complex to autonomously replicating DNA sequences. Cell Cycle. Vol. Mar 2005;4(3): 494-500 (2005 ) , Publication ID: 15711121 .

Biswas-Fiss EE, Khopde SM, Biswas S The Mcm467 complex of Saccharomyces cerevisiae is preferentially activated by autonomously replicating DNA sequences. Biochemistry. Vol. Mar 1 2005;44(8): 2916-2925 (2005 ) , Publication ID: 15723534 .

Biswas S, Flowers S, Biswas-Fiss EE Quantitative analysis of nucleotide modulation of DNA binding by DnaC protein of Escherichia coli. Biochem J. Vol. May 1 2004;379(Pt 3): 553-562 (2004 ) , Publication ID: 14715083 .

Mitkova AV, Khopde SM, Biswas S Mechanism and stoichiometry of interaction of DnaG primase with DnaB helicase of Escherichia coli in RNA primer synthesis. Journal of Biological Chemistry. Vol. 278: 52253-52261 (2003 ) , Publication ID: 14557266 .

Flowers S, Biswas EE, Biswas S Conformational dynamics of DnaB helicase upon DNA and nucleotide binding analysis by intrinsic tryptophan fluorescence quenching. Biochemistry. Vol. 42: 1910-1921 (2003 ) , Publication ID: 12590577 .

Biswas S, Khopde SM, Zhu FX, Biswas EE Subunit interactions in the assembly of Saccharomyces cerevisiae DNA polymerase alpha. Nucleic Acids Research. Vol. 31: 2056-2065 (2003 ) , Publication ID: 12682356 .

Biswas S, Khopde SM, Zhu Fx F, Biswas EE Subunit interactions in the assembly of Saccharomyces cerevisiae DNA polymerase alpha. Nucleic Acids Res. Vol. Apr 15 2003;31(8): 2056-2065 (2003 ) .

Suarez T, Biswas S, Biswas EE Biochemical defects in retina-specific human ATP binding cassette transporter nucleotide binding domain 1 mutants associated with macular degeneration. Journal of Biological Chemistry. Vol. 277: 21759-21767 (2002 ) , Publication ID: 11919200 .

Khopde S, Biswas EE, Biswas S Affinity and sequence specificity of DNA binding and site selection for primer synthesis by Escherichia coli primase. Biochemistry. Vol. 41: 14820-14830 (2002 ) , Publication ID: 12475230 .

Biswas EE, Chen PH, Biswas S Modulation of enzymatic activities of Escherichia coli DnaB helicase by single-stranded DNA-binding proteins. Nucleic Acids Res. Vol. 30: 2809-2816 (2002 ) , Publication ID: 12087164 .

Biswas EE, Biswas S Structure-function analysis of macular dystrophy associated mutations influencing the second nucelotide binding domain of the human retinal ABC transporter. Investigative Ophthalmology & Visual Science. Vol. May 2002;43: U313-U313 (2002 ) .

Suarez-Cortes TM, Biswas EE, Biswas S Biochemical analysis of genetic mutations related to visual disorders in the NBD1 domain of ABC transporter (ABCR). Investigative Ophthalmology & Visual Science. Vol. May 2002;43: U314-U314 (2002 ) .

Mitkova AV, Biswas EE, Biswas S Cell cycle specific plasmid DNA replication in the nuclear extract of Saccharomyces cerevisiae modulation by replication protein A and proliferating cell nuclear antigen. Biochemistry. Vol. 41: 5255-5265 (2002 ) , Publication ID: 11955075 .

Biswas S, Biswas EE Functional analysis of genetic mutations in the nucleotide binding domains of the human retinal ABC transporter. Investigative Ophthalmology & Visual Science. Vol. Mar 15 2001;42(4): S653-S653 (2001 ) .

Biswas EE, Biswas S Nucleotide binding domain 1 (NBD1) of the human retinal ABC transporter gene (ABCR). Cloning, expression and characterization. Investigative Ophthalmology & Visual Science. Vol. Mar 15 2001;42(4): S653-S653 (2001 ) .

Biswas EE, Nagele RG, Biswas S A novel human hexameric DNA helicase: expression, purification and characterization. Nucleic Acids Res. Vol. Apr 15 2001;29(8): 1733-1740 (2001 ) .

Biswas EE, Biswas S Cloning and expression of nucleotide binding domains of the human retinal ATP transporter (ABCR) gene. Investigative Ophthalmology & Visual Science. Vol. Mar 15 2000;41(4): S144-S144 (2000 ) .

Biswas EE, Biswas SB The C-terminal nucleotide binding domain of the human retinal ABCR protein is an adenosine triphosphatase. Biochemistry. Vol. 39: 15879-15886 (2000 ) , Publication ID: 11123914 .

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Grants and Contracts

Title: Anthrax DNA helicase and primase inhibitors for Biodefense
Sponsor: Natonal Institutes of Allergy & Infectious Diseases/NIH
Effective Date(s): 2005 - Ongoing
Role: Joint Principal Investigator

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Research Areas

Mechanism and Regulation of Eukaryotic DNA Replication: Initiation of DNA replication is a pivotal step in the chromosomal DNA replication and proliferation of normal as well as cancer cells. A clear mechanistic understanding of this process is important, as it may help shed light on diseases involving abnormal cell proliferation as well as normal cell proliferation in eukaryotes. We have developed and partially characterized an ORC activated in vitro system for DNA synthesis using nuclear extracts obtained from synchronized yeast cells. Our preliminary studies demonstrate that in this in vitro system (i) DNA synthesis is dependent upon Mcm467 helicase, (ii) DNA synthesis is stimulated several fold by the addition of exogenous purified ORC, (iii) DNA synthesis demonstrates ARS dependency in the presence of ORC, and (iv) synthesis is cell-cycle dependent. In this proposal, we shall utilize this in vitro system, along with approaches to probe the dynamics of protein-protein, protein-DNA interactions that take place during initiation of DNA replication in the yeast, S. cerevisiae. We will analyze Mcm protein-DNA interactions, a possible key step in the regulation and assembly of pre-RC and RC complex formation. We will analyze how MCM protein-DNA interaction is modulated and how it contributes to remodeling of MCM protein complexes in the replication fork. We will test the hypothesis that the replication origin or ARS sequences play significant roles in modulating DNA-Mcm complex interactions. We will examine the dynamics of interaction and assembly of pre-RC and RC at the origin of DNA replication in S. cerevisiae. Collectively, ORC, MCM and cdc6 proteins appear to emulate DnaA, DnaB and DnaC of E. coli. Through a combination of biochemical and biophysical analyses, we will examine their roles.

DNA helicase and primase inhibitors for New Antibiotics: The increasing prevalence of antibiotic-resistant strains of bacterial pathogens represents a major unmet medical need. Naturally occuring or intentionally engineered drug-resistance in biothreat agents is also a serious risk for biodefense. The development of new antibiotics against unexploited targets with novel mechanisms of action is a vital part of the solution to these problems because such antibiotics will not be affected by pre-existing resistance alleles. Two essential components of the DNA replication pathway, helicase and primase, which act early and catalyze a rate-limiting step in replication, are currently untargeted by antibacterials. The goal of this project is to discover new inhibitors of the helicase or primase activities in bacterial DNA replication and develop them into antibiotics for biodefense as well as for clinical applications.

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