Summary
Mini CV
- 1988 - B.Sc. in Physics, Peking University, China
- 1995 - Ph.D. in Physics, SUNY @ Stony Brook, USA
- 1995 - 1997 postdoctoral fellow, Harvard University
- 1997 - 2000 postdoctoral Fellow, Cancer Research UK
- 2001 - 2005 Lecturer, Imperial College London
- 2005 - 2008 Reader, Imperial College London
- 2008 - 2014, Professor of Macromolecular Structure and Function, Department of Life Sciences, Imperial College London
- 2014 - present, Professor, Section of Structural Biology, Department of Infectious Disease, Imperial College London
- 2011 - 2014, Director, Centre for Structural Biology, Imperial College london
- 2019 - 2023, Satellite Group Leader, Francis Crick Institute
- 2023 - present, Secondment Group Leader, Francis Crick Institute
Research
Please visit Structural Biology Section website
My research programme focuses on unravelling the mechanisms of macromolecular machines using a range of structural biology techniques including X-ray crystallography and cryo-electron microscopy. I am particularly interested in large macromolecular assemblies invovled in DNA processing as well as the AAA (ATPase Associated with diverse cellular Activities) protein family. At present my research focuses on three main areas: key components in DNA damage response, transcriptional regulation in bacteria, structrue and mechanism of multifunctional p97.
Structures and Mechanisms of key components in the DNA damage response- DNA is exposed to toxic chemicals, UV and other radiation and consequently tens of thousands of DNA bases are damaged each day in every human cell. Cells have developed sophisticated systems using multi-subunit macromolecular complexes to detect, process and repair this damage in a highly controlled and coordinated fashion. We are currently using a multi-disciplinary approach to provide a molecular understanding of some of the key events including signaling, chromatin remodeling and DNA damage repair itself. This project is in collaboration with Prof. Peter Burgers, Washington University in St Louis, Prof. Dale Wigley FRS and Dr. Stephen West FRS, Cancer Research UK.
Transcription regulation - One of my main research areas is to understand the transcription regulation, in particular the activation/initiation process. We use the bacterial sigma54 dependent system as a simplified model system to establish the structural basis for the transcription initiation, in particular how double stranded DNA is melted out and template strand delivered into the activate site of RNA polymerase. We are also interested in how this process is controlled by the activator proteins belonging to the large AAA ATPase family and how these activators are regulated by upstream cellular signals. This project is in collaboration with Prof. Martin Buck FRS, Imperial College.
Selected recent publications
Yates LA, Tannous EA, Morgan RM, Burgers PM, Zhang X (2023). “A DNA damage-induced phosphorylation circuit enhances Mec1ATR-Ddc2ATRIP recruitment to Replication Protein A. Proc Natl Acad Sci USA, 120(14):e2300150120.
Ye F, Gao F, Liu X, Buck M and Zhang X (2022). “Mechanisms of DNA opening revealed in AAA transcription complex structure”. Science Advances,8(51):eadd3479.
Tannous EA#, Yates LA#, Zhang X* and Burgers PM* (2021) “Mechanism of Auto-inhibition and Activation of Mec1ATR Checkpoint Kinase”. Nat Struct Mol Biol, 28(1):50-61.
Yates LA, Aramayo RJ, Pokhrel N, Caldwell CC, Kaplan JA, Perera RL, Spies M, Antony E, Zhang X (2018). "A structural and dynamic model for the assembly of Replication Protein A on single-stranded DNA". Nat Commun. 9(1):5447.
Ayala R, Willhoft O, Aramayo RJ, Wilkinson M, McCormack EA, Ocloo L, Wigley DB, Zhang X(2018). “Structure and regulation of the human INO80-nucleosome complex”. Nature. 556(7701):391-395.
Glyde R, Ye F, Jovanovic M, Kotta-Loizou I, Buck M and Zhang X (2018). "Structures of Bacterial RNA Polymerase Complexes Reveal the Mechanism of DNA Loading and Transcription Initiation". Mol Cell. 70(6):1111-1120.
Aramayo RJ, Willhoft O, Ayala R, Bythell-Douglas R, Wigley DB and Zhang X (2018). "Cryo-EM structures of the human INO80 chromatin-remodelling complex". Nat. Struct. Mol Biol. 25(1):37-44
Glyde R, Ye F, Darbari VC, Zhang N, Buck M and Zhang X (2017). “Structures of RNA Polymerase Closed and Intermediate Complexes Reveal Mechanisms of DNA Opening and Transcription Initiation”. Mol Cell. 67(1):106-116
Yang Y, Darbari VC, Zhang N, Lu D, Glyde R, Wang YP, Winkelman JT, Gourse RL, Murakami KS, Buck M, Zhang X (2015). "Structures of the RNA polymerase-s54 reveal new and conserved regulatory strategies". Science, 349:882-885
Shahid T, Soroka J, Kong EH, Malivert L, McIlwraith MJ, Pape T, West SC, Zhang X (2014) " Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor". Nat. Struct Mol Biol doi: 10.1038/nsmb.2899
Further Information
Elected Member of the European Molecular Biology Organisation (2016)
Wellcome Trust Investigator (2019)
Wellcome Trust Senior Investigator (2012)
Fellow of the Royal Society of Biology (2011)
Royal Society Wolfson Merit Research Award (2011)
Human Frontier Science Programme Young Investigator Award (2002-2005)
First Recipient of Gertrude Goldhabor Women in Physics Award (1993)
Selected Publications
Journal Articles
Glyde R, Ye F, Jovanovic M, et al., 2018, Structures of bacterial RNA polymerase complexes reveal mechanisms of DNA loading and transcription initiation, Molecular Cell, Vol:70, ISSN:1097-2765, Pages:1111-1120.e3
Zhang N, Darbari VC, Glyde R, et al., 2016, The bacterial enhancer-dependent RNA polymerase, Biochemical Journal, Vol:473, ISSN:1470-8728, Pages:3741-3753
Zhang N, Jovanovic G, McDonald C, et al., 2016, Transcription regulation and membrane stress management in enterobacterial pathogens, Advances in Experimental Medicine and Biology, Vol:915, ISSN:0065-2598, Pages:207-230
Zhang N, Schaefer J, Sharma A, et al., 2015, Mutations in RNA Polymerase Bridge Helix and Switch Regions Affect Active-Site Networks and Transcript-Assisted Hydrolysis, Journal of Molecular Biology, Vol:427, ISSN:1089-8638, Pages:3516-3526
Liu J, Yang J, Wen J, et al., 2014, Mutational analysis of dimeric linkers in peri- and cytoplasmic domains of histidine kinase DctB reveals their functional roles in signal transduction, Open Biology, Vol:4, ISSN:2046-2441
Ewens CA, Panico S, Kloppsteck P, et al., 2014, The p97-FAF1 Protein Complex Reveals a Common Mode of p97 Adaptor Binding, Journal of Biological Chemistry, Vol:289, Pages:12077-12084
Sharma A, Leach RN, Gell C, et al., 2014, Domain movements of the enhancer-dependent sigma factor drive DNA delivery into the RNA polymerase active site: insights from single molecule studies, Nucleic Acids Research, Vol:42, ISSN:0305-1048, Pages:5177-5190
Yeung HO, Foerster A, Bebeacua C, et al., 2014, Inter-ring rotations of AAA ATPase p97 revealed by electron cryomicroscopy, Open Biology, Vol:4, ISSN:2046-2441
Darbari VC, Lawton E, Lu D, et al., 2014, Molecular basis of nucleotide-dependent substrate engagement and remodeling by an AAA plus activator, Nucleic Acids Research, Vol:42, ISSN:0305-1048, Pages:9249-9261
Saravanan M, Wuerges J, Bose D, et al., 2012, Interactions between the nucleosome histone core and Arp8 in the INO80 chromatin remodeling complex, Proceedings of the National Academy of Sciences of the United States of America, Vol:109, ISSN:0027-8424, Pages:20883-20888
Fillet S, Daniels C, Pini C, et al., 2012, Transcriptional control of the main aromatic hydrocarbon efflux pump in <i>Pseudomonas</i>, Environmental Microbiology Reports, Vol:4, ISSN:1758-2229, Pages:158-167
Niwa H, Ewens CA, Tsang C, et al., 2012, The Role of the N-Domain in the ATPase Activity of the Mammalian AAA ATPase p97/VCP, Journal of Biological Chemistry, Vol:287, Pages:8561-8570
Kloppsteck P, Ewens CA, Foerster A, et al., 2012, Regulation of p97 in the ubiquitin-proteasome system by the UBX protein-family, Biochimica et Biophysica Acta-Molecular Cell Research, Vol:1823, ISSN:0167-4889, Pages:125-129
Joly N, Zhang N, Buck M, et al., 2012, Coupling AAA protein function to regulated gene expression, Biochimica et Biophysica Acta-Molecular Cell Research, Vol:1823, ISSN:0167-4889, Pages:108-116
Fillet S, Krell T, Morel B, et al., 2011, Intramolecular signal transmission in a tetrameric repressor of the IclR family, Proceedings of the National Academy of Sciences of Usa, Vol:37, Pages:15372-15377
Bush M, Ghosh T, Tucker N, et al., 2011, Transcriptional regulation by the dedicated nitric oxide sensor, NorR: a route towards NO detoxification, Biochemical Society Transactions, Vol:39, ISSN:0300-5127, Pages:289-293
Jovanovic M, Burrows PC, Bose D, et al., 2011, Activity map of the Escherichia coli RNA polymerase bridge helix, J Biol Chem, Vol:286, ISSN:1083-351X, Pages:14469-14479
Sweeney TR, Cisnetto V, Bose D, et al., 2010, Foot-and-Mouth Disease Virus 2C Is a Hexameric AAA plus Protein with a Coordinated ATP Hydrolysis Mechanism, Journal of Biological Chemistry, Vol:285, Pages:24347-24359
Daniels C, Daddaoua A, Lu D, et al., 2010, Domain Cross-talk during Effector Binding to the Multidrug Binding TTGR Regulator, Journal of Biological Chemistry, Vol:285, Pages:21372-21381
Nan B, Liu X, Zhou Y, et al., 2010, From signal perception to signal transduction: ligand-induced dimeric switch of DctB sensory domain in solution, Molecular Microbiology, Vol:75, ISSN:0950-382X, Pages:1484-1494
Ewens CA, Kloppsteck P, Foerster A, et al., 2010, Structural and functional implications of phosphorylation and acetylation in the regulation of the AAA+ protein p97, Biochemistry and Cell Biology-Biochimie et Biologie Cellulaire, Vol:88, ISSN:0829-8211, Pages:41-48
Carmen Herrera M, Krell T, Zhang X, et al., 2009, PhhR Binds to Target Sequences at Different Distances with Respect to RNA Polymerase in Order to Activate Transcription, Journal of Molecular Biology, Vol:394, ISSN:0022-2836, Pages:576-586
Burrows PC, Schumacher J, Amartey S, et al., 2009, Functional roles of the pre-sensor I insertion sequence in an AAA plus bacterial enhancer binding protein, Molecular Microbiology, Vol:73, ISSN:0950-382X, Pages:519-533
Xu Y, Liu M, Simpson PJ, et al., 2009, Automated Assignment in Selectively Methyl-Labeled Proteins, Journal of the American Chemical Society, Vol:131, ISSN:0002-7863, Pages:9480-+
Bose D, Pape T, Burrows PC, et al., 2008, Organization of an Activator-Bound RNA Polymerase Holoenzyme, Molecular Cell, Vol:32, ISSN:1097-2765, Pages:337-346
Zhang X, Wigley DB, 2008, The 'glutamate switch' provides a link between ATPase activity and ligand binding in AAA plus proteins, Nature Structural and Molecular Biology, Vol:15, ISSN:1545-9985, Pages:1223-1227
Briggs LC, Baldwin GS, Miyata N, et al., 2008, Analysis of nucleotide binding to p97 reveals the properties of a tandem AAA hexameric ATPase, Journal of Biological Chemistry, Vol:283, Pages:13745-13752
Joly N, Rappas M, Buck M, et al., 2008, Trapping of a transcription complex using a new nucleotide analogue: AMP aluminium fluoride, Journal of Molecular Biology, Vol:375, ISSN:0022-2836, Pages:1206-1211
Bose D, Joly N, Pape T, et al., 2008, Dissecting the ATP hydrolysis pathway of bacterial enhancer-binding proteins, Biochemical Society Transactions, Vol:36, ISSN:0300-5127, Pages:83-88
Yeung HO, Kloppsteck P, Niwa H, et al., 2008, Insights into adaptor binding to the AAA protein p97, Biochemical Society Transactions, Vol:36, ISSN:0300-5127, Pages:62-67
Alguel Y, Meng C, Teran W, et al., 2007, Crystal structures of multidrug binding protein TtgR in complex with antibiotics and plant antimicrobials, Journal of Molecular Biology, Vol:369, ISSN:0022-2836, Pages:829-840
Rappas M, Bose D, Zhang X, 2007, Bacterial enhancer-binding proteins:: unlocking σ<SUP>54</SUP>-dependent gene transcription, Current Opinion in Structural Biology, Vol:17, ISSN:0959-440X, Pages:110-116
Pye VE, Beuron F, Keetch CA, et al., 2007, Structural insights into the p97-Ufd1-NpI4 complex, Proceedings of the National Academy of Sciences of the United States of America, Vol:104, ISSN:0027-8424, Pages:467-472
Pye VE, Dreveny I, Briggs LC, et al., 2006, Going through the motions: The ATPase cycle of p97, Journal of Structural Biology, Vol:156, ISSN:1047-8477, Pages:12-28
Rappas M, Schumacher J, Niwa H, et al., 2006, Structural basis of the nucleotide driven conformational changes in the AAA<SUP>+</SUP> domain of transcription activator PspF, Journal of Molecular Biology, Vol:357, ISSN:0022-2836, Pages:481-492
Beuron F, Dreveny I, Yuan X, et al., 2006, Conformational changes in the AAA ATPase p97-p47 adaptor complex, EMBO Journal, Vol:25, ISSN:0261-4189, Pages:1967-1976
Ramos JL, Martínez-Bueno M, Molina-Henares AJ, et al., 2005, The TetR family of transcriptional repressors, Microbiology and Molecular Biology Reviews, Vol:69, ISSN:1092-2172, Pages:326-+
Rappas M, Schumacher J, Beuron F, et al., 2005, Structural insights into the activity of enhancer-binding proteins, Science, Vol:307, ISSN:0036-8075, Pages:1972-1975
Dreveny I, Kondo H, Uchiyama K, et al., 2004, Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47, EMBO Journal, Vol:23, ISSN:0261-4189, Pages:1030-1039
Huyton T, Pye VE, Briggs LC, et al., 2003, The crystal structure of murine p97/VCP at 3.6 Å, Journal of Structural Biology, Vol:144, ISSN:1047-8477, Pages:337-348
Bordes P, Wigneshweraraj SR, Schumacher J, et al., 2003, The ATP hydrolyzing transcription activator phage shock protein F of <i>Escherichia coli</i>:: Identifying a surface that binds σ<SUP>54</SUP>, Proceedings of the National Academy of Sciences of the United States of America, Vol:100, ISSN:0027-8424, Pages:2278-2283
Zhang XD, Shaw A, Bates PA, et al., 2000, Structure of the AAA ATPase p97, Molecular Cell, Vol:6, ISSN:1097-2765, Pages:1473-1484
Huyton T, Bates PA, Zhang XD, et al., 2000, The BRCA1 C-terminal domain: structure and function, Mutation Research - DNA Repair, Vol:460, ISSN:0921-8777, Pages:319-332
Zhang XD, Moréra S, Bates PA, et al., 1998, Structure of an XRCC1 BRCT domain:: a new protein-protein interaction module, EMBO Journal, Vol:17, ISSN:0261-4189, Pages:6404-6411