个人简介

Ph.D. 2005 Wesleyan University (CT) Postdoctoral 2005-06 Johns Hopkins University (MD) Postdoctoral 2006-10 Washington University School of Medicine (MO) Instructor 2010-12 Washington University School of Medicine (MO)

研究领域

Biochemistry

Our research group is interested in the mechanism of action of DNA binding proteins that function in DNA repair, recombination and transcription. We use a broad tool kit encompassing biophysical (spectroscopy and rapid kinetics), structural (x-ray crystallography), and molecular biological techniques to investigate the activities of these complex molecular machines. This multi-faceted approach enables us to build quantitative, structure-based, biological models towards understanding their roles in disease development. Our proteins of interest function in the following pathways: Homologous Recombination, Genomic Instability and Cancer: Unrepaired mutations in DNA cause genomic instability which ultimately results in cancer. We are interested in the DNA repair process called Homologous Recombination (HR), the primary mechanism through which cells repair mutations that arise due to breaks in the DNA. HR is the quintessential biological ‘double-edged sword’ - while HR is a critical DNA repair process, unregulated or excessive HR causes harmful gene rearrangements that also result in cancer and aging. Our lab is interested in the overall mechanism of HR and how it is regulated in the cell. HR proceeds through a carefully orchestrated sequence of events – initiation, pre-synaptic filament formation, synapsis and strand invasion, replication and finally resolution. The Rad51 recombinase forms a cooperative helical filament on the resected ssDNA at the ‘pre-synaptic filament’ step which then drives forward the rest of the HR process. Our initial interest is in understanding the dynamics of the Rad51 filament at this step.In particular, how does the Rad51 protein nucleate on ssDNA and form the filament?Pro- and anti-HR regulators act by controlling the dynamics of the Rad51 filament. The Srs2 helicase is a negative regulator and functions by disassembling the filament. The Rad55-Rad57 complex is a positive regulator and functions by stabilizing the Rad51 filament. Each of these three proteins function by coupling ATP binding and hydrolysis to their activity on DNA; moreover, all three proteins physically interact with each other during HR. Projects in the lab address the following specific questions: 1. How does Rad51 nucleate and form the pre-synaptic filament? 2. How does the Srs2 helicase function as an anti-recombinase? 3. How does the Rad55-Rad57 complex function as a pro-recombinase? 4. Investigate the structural and biophysical properties of all these proteins. 5. How are the activities of these proteins spatio-temporally separated in the cell and how are they regulated by the cell cycle and DNA damage specific checkpoint responses? Senataxin, Transcription Termination and Amyotrophic Lateral Sclerosis (ALS): ALS, also known as Lou Gehrig’s disease, is a result of damage to the nerve cells in the brain and the spinal cord that controls voluntary muscle movement. Patients with mutations in the SETX gene develop a juvenile form of ALS (ALS4) and Ataxia Oculomotor Apraxia type 2 (AOA2). The SETX gene codes for a motor protein called Senataxin which is thought to function in transcription termination. We are interested in the mechanism of action of Senataxin, its interacting partners and its regulation in the cells. More interestingly, how do mutations in Senataxin result in ALS and what is the molecular basis for disease onset? Projects in the lab will address the following questions: 1. How does the Senataxin helicase bind, move and/or unwind DNA/RNA? 2. How does Senataxin couple ATP binding and hydrolysis to its activities on DNA/RNA? 3. What is the structural-domain organization of Senataxin and what are their functional roles? 4. How does Senataxin function in transcription termination? 5. What are Senataxin’s binding partners and how/when do they affect its activity? 6. How do SETX mutations that lead to ALS affect the function of Senataxin?

近期论文

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Kozlov A.G., Weiland E., Mittal A., Waldman V., Antony E., Fazio N., Pappu R.V. and Lohman T.M. Intrinsically disordered C-terminal tails of E. coli single stranded DNA binding protein regulate cooperative binding to single stranded DNA. J. Mol. Biol. 2015. In Press. Lytle, A.K., Origanti, S., Vongermeten, G., and Antony E. Context dependent remodeling of Rad51-DNA complexes by Srs2 is mediated by a specific protein-protein interaction. J. Mol. Biol. 2014. 426:1888-1897. Duval S., Danyal K., Shaw S., Dean D.R., Hoffman B.M., Antony E*. and Seefeldt L.C.* Establishing the order of electron transfer and ATP hydrolysis in Nitrogenase . PNAS. 2013. 110:16414-16419 (*Co-Corresponding Authors). Antony E., Weiland, E, Yuan Q., Manhart, C.M., Nguyen B., Kozlov A.K., McHenry S.S., and Lohman T.M. Multiple C-terminal tails within a single E. coli SSB homotetramer coordinate DNA replication and repair. J. Mol. Biol. 2013. Yupeng Q., Antony E., Doganay S., Koh H.R., Lohman T.M., and Myong S. Srs2 prevents Rad51 filament formation by repetitive motion on DNA. Nature Communications. 2013. 4:2281 Antony E., Kozlov A.J., Nguyen B., and Lohman T.M. Plasmodium falciparum SSB tetramer binds single-stranded DNA only in a fully wrapped mode. J. Mol. Biol. 2012. 420: 284-295. Featured as cover Antony E., Weiland E.A., Korolev S., and Lohman T.M. Plasmodium falciparum SSB tetramer wraps single-stranded DNA with similar topology but opposite polarity to E. coli SSB. J. Mol. Biol. 2012. 420: 269-283. Majka A.M., Maluf K.M., Antony E., and Lohman T.M. Self-assembly of E. coli MutL and its complexes with DNA. Biochemistry. 2011.37:7868-80 Antony E., and Lohman T.M. "Non-hexameric SF1 DNA helicases and translocases". Encyclopedia of Biological Chemistry, (2nd edition) W.J. Lennarz and M.D. Lane, eds. Elsevier Science (2010). Antony E., Tomko E.J., Xiao Q.*, Krejci L., Lohman T.M., and Ellenberger T.E. Srs2 dismantles Rad51 filaments by a protein-protein interaction triggering ATP turnover and dissociation of Rad51 from DNA. Molecular Cell. 2009. 35:105-115. Antony E., Khubchandani S., Chen S., and Hingorani M.M. Contribution of Msh2 and Msh6 subunits to the asymmetric ATPase and DNA mismatch binding activities of Saccharomyces cerevisiae Msh2-Msh6 mismatch repair protein. DNA Repair. 2006. 5(2):153-62. Zito C.R. *, Antony E.*, Hunt J.F., Oliver D.B., and Hingorani M.M. Role of a conserved glutamate residue in the Escherichia coli SecA ATPase mechanism. J. Biol. Chem. 2005. 280:14611-14619 (* Co-first authors). Antony E. and Hingorani M.M. Asymmetric ATP binding and hydrolysis activity of the Thermus aquaticus MutS dimer is key to modulation of its interactions with mismatched DNA. Biochemistry. 2004. 43:13115-13128. Antony E. and Hingorani M.M. Mismatch recognition-coupled stabilization of Msh2-Msh6 in an ATP-bound state at the initiation of DNA repair. Biochemistry. 2003. 42:7682-93. Finkelstein J., Antony E., Hingorani M.M., and O'Donnell M. Overproduction and analysis of eukaryotic multiprotein complexes in Escherichia coli using a dual-vector strategy. Anal. Biochem. 2003. 319:78-87.