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Panos Soultanas

Professor of Biological Chemistry, Faculty of Science

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Biography

Panos Soultanas was born in Thessaloniki capital of the Greek province of Macedonia and came to the UK in 1982 to pursue A-level and University studies. He graduated from the University of Sheffield with a BSc honours degree (Biochemistry & Microbiology) in 1987 and completed his PhD studies in Biochemistry & Molecular Biology at the same University in 1990. His first post-doctoral position was on site-specific recombination at the University of Bristol (1990-1994), under the supervision of Prof. Steve Halford (FRS). After spending 12 months in the Greek Army (obligatory military service) he then moved to the University of Crete and spent a year and a half working on gene silencers of the gamma-globin locus. In September 1996 he moved to the University of Oxford where he worked in the group of Dr. Dale B. Wigley (FRS) on the structure and function relationships of DNA helicases. In September 2000 he was appointed as a lecturer in Chemical Biology at the School of Chemistry, University of Nottingham. In August 2004 he was promoted to Associate Professor and Reader in Biological Chemistry and from January 2008 to a Chair in Biological Chemistry.

In Dec. 2011, Panos was elected a Fellow of the Society of Biology (FSB) http://www.societyofbiology.org/home and in Sept. 2012 Panos was accepted on the register of Chartered Biologists (CBiol) https://myaccount.societyofbiology.org/index.php?a=cbiol_info

Panos was a winner of the Wellcome Trust sponsored science promotion event 'I'm a scientist get me out of here' in June 2010;

http://www.rsc.org/Education/EiC/Restricted/2010/September/ImAScientistGetMeOutOfHere.asp

Panos has accepted an external examiner post (2012-2016) at Queen's University, Belfast for the BSc (Hons) Biochemistry, BSc (Hons) Molecular Biology and BSc Genetics degree courses.

Panos has been appointed a member of the BBSRC Pool of Experts (01/01/2012 to 31/05/2015)

Panos has joined the editorial board of the new journal scientifica (http://www.scientifica.com)

About Scientifica

Scientifica is a peer-reviewed open access journal that publishes research and review articles in a wide range of subjects within the medical sciences, life sciences, and environmental sciences. The journal's Editorial Board and Contents are divided into a number of subject areas, however articles published in the journal may appear in multiple subject areas.

Scientifica is a division of Hindawi Publishing Corporation, a pioneering open access scholarly publisher with over 300 academic journals.

Expertise Summary

Work in our lab is featured in the 'News, features and events' section of the BBSRC:

http://www.bbsrc.ac.uk/news/research-technologies/2011/110223-pr-dna-replication-derailment.aspx

Our Nature manuscript on Replication-Transcription collisions has been featured in a post-publication peer review by the Faculty of 100 (F100) on

http://f1000.com/8941959

and on science daily

http://www.sciencedaily.com/releases/2011/02/110224103043.htm

Read Panos' review "Elongation; primases & helicases" for the Encyclopedia of Molecular Life Sciences (Springer) at

http://www.springerreference.com/docs/html/chapterdbid/333587.html

My interests and expertise lie in the area of mechanistic Biochemistry and in particular bacterial DNA replication/priming, DNA repair and site-specific recombination. I joined the School of Chemistry in September 2000 and since then I have built up a dynamic research group with good publication record. Our research encompasses the areas of Chemical Biology, Biochemistry and Molecular Biology with emphasis on bacterial DNA replication that is the most fundamental biological process, directly relevant to cancer and genetically based diseases. We are also exploring novel ideas across the areas of Bioorganic Chemistry and Life Sciences for the development of new antibacterial drugs that target DNA replication to combat the ever-increasing problem of antibiotic resistance.

Collaborative work (Chris Hayes) on novel modifications on the backbone of DNA revealed the importance of rotational DNA backbone freedom for the action of PcrA DNA helicase. This is a new concept and a property of DNA that has not been examined in detail before. This property could potentially be exploited in many other biological systems to develop new gene therapy approaches against cancer and genetic diseases. As a result of these studies collaborations in this area have developed with Pavel Janscak's group (Zurich) in the area of DNA repair and ageing.

Our collaboration on Atomic Force Microscopy imaging of biomolecules (Clive Roberts and Stephanie Allen) has also been very successful. The structural architecture of the helicase/clamp-loader complex, the DnaB primosomal protein from B. subtilis and the structure of the helicase/primase complex have been revealed by AFM. The NMR solution structure of the C-terminal domain of the bacterial primase enzyme that is responsible for the functional interaction with the replicative helicase (collaboration with Prof. Jon Waltho) has been solved. These studies have contributed towards revealing the structure of the complete replisome. The replisome is the most important universal biological machine responsible for replicating DNA and propagating life. Recent collaborative studies with Steve Hinrichs and Mark Griep (Nebraska, USA) probed a variety of structure/function relationships in bacterial helicase-primase systems. Our studies on the B. subtilis replication initiation proteins DnaD and DnaB revealed that these proteins have important DNA remodelling activities that might be relevant in primosomal assembly and genome architecture.

My emphasis is on inter-disciplinarity and collaborations across the board of Life Sciences and Chemistry bringing together different but complementary expertise to carry out cutting-edge biological research. I have linked well with colleagues within my own School (Chris Hayes, Jon Hirst) and substantial collaborations have been developed with colleagues from the Nottigham School of Pharmacy (Clive Roberts, Stephanie Allen, Weng Chan) and Maggie Smith (Aberdeen University). Further links have been established with Prof. Jon Waltho (Sheffield) on NMR protein determination.

Collaborative work on the bacterial helicase-primase interaction has been initiated with Prof. Steven Hinrichs and Dr. Mark Griep (Nebraska, USA) and also with Prof. Nick Dixon (Australia) on the DnaI helicase loader protein. A very successful collaboration with Max Paoli (Pharmacy) on crystallography and structure/function studies of primosomal proteins has resulted in the publication of the DnaD NTD structure. Further collaborations have been established with Prof. Alan Grossman (MIT, Boston) and Wiep Klaas Smits (Leiden, Netherlands).

At the same time, I remain focused avoiding 'dilution' of my research efforts and ensuring our participation in high quality collaborative research. The ever-increasing specialization of research within Life Sciences is making the need for interdisciplinary and collaborative work more pressing. This is recognized fully by the Research Councils and many strategic calls have been announced to foster inter-disciplinarity and cross-collaboration. Life sciences research is entering challenging and competitive times and I am fully committed to being inclusive in my work and developing further productive links with colleagues from other complementary areas in order to tackle important Biological problems.

Marie Curie Fellowships

European Union PhD holders interested in joining Prof. Soultanas' group via Marie Curie or other EU-funded fellowships should also contact Prof. Soultanas directly. Further information on http://ec.europa.eu/research/mariecurieactions/about-mca/actions/ief/index_en.htm

and for the Marie Curie International Incoming Fellowships (IIF) on http://ec.europa.eu/research/mariecurieactions/about-mca/actions/iif/index_en.htm

Potential applicants that want to join the Soultanas lab are welcome to apply.

Other Fellowship programs

Potential postdoctoral scientists who may be interested in joining the lab under different fellowship schemes are encouraged to contact Prof. Soultanas directly. Guidance and direction for the preparation of fellowship applications will be provided.

PhD studentships

PhD positions become available every year in our lab and graduate students interested in pursuing PhD studies should contact directly Prof. Soultanas for further details. Overseas students holding their own funding are welcome to enquire directly with Prof. Soultanas.

Teaching Summary

First year undergraduate organic labs

F14CBE level 4 Chemical Biology and Enzymes

C73MMI level 3 Molecular Microbiology

F12MCM level 2 Introduction to Medicinal Chemistry, Molecular Biology and Microbiology

F14SSB postgraduate Sustainable Synthesis; Biological Approaches

Natural Sciences Synoptic Module (F13SYN)

F11CC1 and F11CC2 Chemical Calculations 1 and 2

Biochemistry & Biological Chemistry (BBC) C720 and C721 Course Director

F13ST2 Special Topics (Nucleic Acids)

Research Summary

Prof. Soultanas' research interests are centered on the dynamics of large multiprotein assemblies like the primosome and replisome, focusing on protein-protein interactions mediated by DNA helicases.… read more

Selected Publications

Current Research

Prof. Soultanas' research interests are centered on the dynamics of large multiprotein assemblies like the primosome and replisome, focusing on protein-protein interactions mediated by DNA helicases. His current research interests include a number of replisomal and primosomal proteins such as PcrA and DnaB helicases, DnaG primase, DnaI replisomal protein, DnaX connector protein in the Gram +ve Bacillus. The lab also has an interest in the Bacillus subtilis DnaD-DnaB-DnaI primosomal cascade. The main focus of the lab is on recapitulating the entire DNA replication system of B. subtilis in vitro.

Additional projects of interest are in the areas of (i) the Shelterin complex that binds to telomeres, (ii) the biochemistry of the Nth AP-endonuclease from B. subtilis (iii) the regulation of DNA replication by the central carbon metabolism in B. subtilis and (iv) cytokine uptake mechanisms in bacteria.

PhD positions become available every year in our lab and graduate students interested in pursuing PhD studies should contact directly Prof. Soultanas for further details. Overseas students holding their own funding are welcome to enquire directly with Prof. Soultanas.

European Union PhD holders interested in joining Prof. Soultanas' group via Marie Curie or other EU-funded fellowships should also contact Prof. Soultanas directly. The Marie Curie Intra-European Fellowships (IEF) call for applications for 2012 has been announced on http://ec.europa.eu/research/participants/portal/page/people;efp7_SESSION_ID=DmyYPwNTDBk7vP9vmVQ4m8hgT88Vb9bvXvbjbv15w14nnnrmFpnQ!-1456314273?callIdentifier=FP7-PEOPLE-2012-IEF

and for the Marie Curie International Incoming Fellowships (IIF) on http://ec.europa.eu/research/participants/portal/page/people?callIdentifier=FP7-PEOPLE-2012-IIF

Potential applicants that want to join the Soultanas lab are welcome to apply.

New discovery; Cytokine uptake by bacteria

http://rsob.royalsocietypublishing.org/content/3/10/130048.short

http://royalsociety.org/news/2013/bacteria-hijack/

http://www.nottingham.ac.uk/news/pressreleases/2013/october/re-writing-the-research-on-treatment-of-infection.aspx

Past Research

Prof. Soultanas has made significant contributions in these fields and has now established a dynamic research group, consistent publication output in the past 11 years and strong collaborative links with groups in the USA (MIT and Nebraska), Netherlands (Leiden), France (Paris) and in the UK (Bristol, Sheffield, Leeds and Birmingham, Southampton). A brief overview of his research achievements is presented below.

Helicase translocation along the DNA: Novel DNA backbone modifications (vinylphosphonate dinucleotide linkages) were used to reveal the role of rotational backbone freedom on helicase translocation and DNA unwinding, as well as the action of nucleases. PS's group discovered that vinylphosphonate modifications restrict rotational backbone flexibility and inhibit DNA unwinding by DNA helicases (PcrA, the Bloom and Werner syndrome DNA helicases). PS examined the effects of such linkages on the activities of exonuclease III, mung bean nuclease and DNA pol I, and discovered that 4 tandem vinylphosphonate modifications inhibit the action of DNA pol I but do not confer resistance to nucleases. The group is now using such modifications to investigate RNA polymerase-DNA interactions (ongoing work).

The Bacillus subtilis helicase loader DnaI: Replicative ring helicases are loaded onto the DNA by specialized enzymes known as helicase loaders. PS's studies on the B. subtilis helicase loader DnaI established a functional interaction with the B. stearothermophilus DnaB helicase which involves a Zn-coordinating module in the N-terminal domain of DnaI. In response to binding of the helicase the N-terminal domain acts as a molecular switch regulating access to the single stranded DNA binding site located in the C-terminal domain of DnaI.

The B. subtilis clamp-loader protein DnaX: The processivity clamp of the replisome known as the b polypeptide is loaded onto the DNA by the clamp loader, a multi-protein complex with the DnaX protein being its major component. DnaX acts as a connector that links the leading and lagging strand polymerases with the replicative helicase. PS's group provided the first AFM-images of the DnaB-DnaX complex and suggested a structural model. They revealed that L381 of the B. subtilis DnaX is a crucial residue for pentamerization and helicase binding. In gram negative bacteria the DnaX protein is found in two forms, a full length τ protein and a shorter polypeptide known as γ. The current literature suggests that only the τ polypeptide is found in gram positive bacteria. They identified a Shine-Dalgarno sequence and a slippage site in the B.subtilis dnaX gene sequence that could induce transcriptional or translational slippage to produce a shorter polypeptide equivalent to the gram negative γ. More detailed investigations will be required to establish unequivocally the presence or absence of a γ polypeptide in B. subtilis.

The B. subtilis primosomal proteins DnaD and DnaB: PS's group was the first to discover that the essential primosomal proteins of B. subtilis, DnaD and DnaB, possess global DNA remodeling activities. DnaD opens up supercoiled DNA and DnaB acts as a lateral compaction protein. DnaD remodels DNA by untwisting and stretching the double helix, eliminating writhe while keeping the linking number constant. Its remodeling function is the sum of a scaffold-forming activity residing in its N-terminal domain and a DNA-binding activity with a further DNA-dependent oligomerisation activity in the C-terminal domain. PS in collaboration with Max Paoli (Nottingham) solved the crystal structure of the scaffold forming N-terminal domain of DnaD and suggested a structural model for the scaffold. In collaboration with Jeremy Craven (Sheffield) PS determined the solution structure of the C-terminal domain and established the structural features that underpin its interaction with DNA. They identified a highly conserved YxxxIxxxW motif likely involved in DNA binding across all DnaD-like proteins. Their bioinformatics studies uncovered a previously undiscovered structural homology between the DnaD and DnaB replication initiation proteins suggesting that they have likely evolved from a common ancestral protein.

The bacterial helicase (DnaB)-primase (DnaG) interaction: In collaboration with Jon Waltho (Sheffield) PS solved the first solution structure of the C-terminal domain of the DnaG primase, responsible for its interaction with the DnaB helicase. The structure revealed a unique and surprising structural homology with the N-terminal domain of DnaB and suggested a mechanism that was probed further. PS discovered that the activities of DnaB and DnaG in the complex are modulated by distinct but overlapping networks of residues, while domain swapping experiments revealed functional interchangeability between the C- and N-terminal domains of DnaG and DnaB, respectively. PS isolated, by yeast three-hybrid screening of a random peptide library, an antagonist peptide that interferes with the DnaB-DnaG interaction. The recognition sites of the B. stearothermophilus DnaG were found to be 5'-CTA-3' and 5'-TTA-3' and the starting ribonucleotide was established to be the ATP complementary to the middle thymine base of the recognition sites. These data have recently been confirmed by collaborative work with the Hinrich and Griep groups (Nebraska, USA), which also revealed that the C-terminal domain of DnaG is not only a structural module mediating the interaction with DnaB but is essential for optimal primer synthesis. PS revealed the molecular basis of initiation specificity in bacteria primase enzymes. A further finding from PS's group showed that the activity of the bacterial primase is modulated allosterically by the clamp loader DnaX protein, and this modulation involves the18 C-terminal residues of DnaX.

The RepD-PcrA molecular motor: PS developed an AFM-based assay to visualize the unwound products from helicase reactions using supercoiled plasmids. With this assay, PS studied the directional loading and stimulation of the PcrA helicase by the plasmid-encoded replication initiator RepD. PS discovered that PcrA is recruited onto the minus strand by a RepD that is covalently attached to the 5'-phosphate group at the nick site, within oriD. Subsequently, PS in collaboration with Mark Dillingham (Bristol) monitored the entire unwinding of a supercoiled plasmid by fluorescence and found that unwinding is processive and directional, and occurs at a speed of ~60 bp/sec. PS discovered that PcrA surprisingly is able to load at a nick independently of RepD but in this case it loads onto the plus strand and translocates non-processively in the opposite direction than that of the PcrA-RepD molecular motor. DNAaseI and ExoIII footprint studies were used to investigate the molecular details of the RepD-mediated PcrA loading at oriD and a novel mechanistic loading model was proposed.

Transcription and replication: In a collaborative study with Steve Busby (Birmingham) PS used AFM to support studies which show that autoregulation of the melR promoter involves four MelR molecules in a nucleoprotein complex that does not form DNA looping. Recently, PS probed conflicts between replication and transcription in collaboration with Alan Grossman (MIT, Boston). Until his research was published in the journal Nature, the assumption in the field was that co-directional replication-transcription collisions are not detrimental to replication. PS's findings revealed that such conflicts are serious enough to warrant the intervention of the replication restart machinery in a process that is PriA-dependent and DnaA-independent. A paper from this work was recently published in Nature and featured the spring 2011 edition of the BBSRC Business magazine.

Cytokine binding and uptake by bacteria: We have discovered an important novel role for cytokines as direct modulators of bacterial behaviour and pathogenicity. Using Neisseria meningitidis as a model organism, we have provided solid evidence that opportunistic bacteria bind and uptake host cytokines which specifically bind the organism's genomic DNA and modulate its transcriptome, virulence expression and ultimately its commensal or pathogenic behaviour.

Future Research

We are interested in the areas of (i) the telomeric Shelterin complex, (ii) the biochemistry of the Nth AP-endonuclease from B. subtilis, (iii) the regulation of DNA replication by central carbon metabolism in B. subtilis, (iv) cytokine uptake by bacteria, (v) lagging strand replication and hand off mechanisms in Bacillus subtilis, (vi) replication initiation mechanisms at the Bacillus subtilis bipartite replication origin, oriC and (vii) Clostridium difficile replication proteins. up u uop cytoki and bybe kaptv) cytokine u and (i, and (iv)

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