Structural Biology of Cell Signalling
Dr Sebastian Guettler’s group is researching the ways in which certain enzymes, known as ADP-ribosyltransferases (ARTs), control cell function.
Professor Sebastian Guettler
Deputy Head of Division:
Structural Biology of Cell Signalling.jpg?sfvrsn=4c485212_1 "Sebastian_Guettler_2 (1)")
Professor Sebastian Guettler is Deputy Head of the Division of Structural Biology. He studies the precise molecular mechanisms of signalling processes central to cancer stem cell function, with a particular interest in Wnt/β-catenin signalling, telomere length homeostasis and their regulation by ADP-ribosylation. He has a long-standing interest in understanding tankyrase, a poly-ADP-ribosyltransferase with roles in both Wnt/β-catenin signalling and telomere maintenance.
Researchers in this group
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Email: [email protected]
I graduated from the University of Southampton, with an integrated Master’s in Biochemistry (MSc). For my bachelor’s project, I investigated the effects of reactive oxygen species and vitamin C on S100A9 aggregation in Alzheimer’s disease. For my Master’s project, I investigated the functional importance of Snap29 for mitosis in Drosophila. For my PhD, I study the molecular mechanisms of telomere maintenance.
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Email: [email protected]
Location: SuttonChelsea
I graduated from the University of Manchester, with a BSc in Biochemistry with industrial experience (IE). I spent my IE at Mayo Clinic in Jacksonville, Florida, investigating mitochondrial dysfunction in disease. In 2020, I joined the ICR to study how tankyrase regulates Wnt/β-catenin signalling utilising genetic techniques.
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Email: [email protected]
Location: Chelsea
I joined Sebastian's lab in August 2023 as a Postdoctoral Fellow to investigate the molecular mechanisms of the Wnt/β-catenin signalling pathway in normal and cancer cells. Prior to joining the ICR, I was a Postdoctoral Research Fellow at the laboratory of Dr Roger Grand at the University of Birmingham, where I also obtained my PhD studying the DNA damage response. My PhD research focussed on the role of CCR4-NOT complex in the DNA damage response (DDR), and how disruption of this complex contributes to transcription-mediated genome instability. My current research mainly focusses on understanding the mechanisms of the β-catenin destruction complex.
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Email: [email protected]
Location: Chelsea
Oviya studied Biotechnology during her undergraduate degree at SRM University, India. She then completed her PhD in Professor Sara Sandin's lab at Nanyang Technological University, Singapore. Oviya joined the ICR as a postdoc in 2019 and is currently studying the function of tankyrase at telomeres.
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I completed my BSc (Hons) in Biology at the University of Auckland, New Zealand, in 2015. I then moved to the Institut de Biologie Structurale in Grenoble, France, for my PhD, working in Dr Irina Gutsche’s group. During my PhD, I used cryo-EM and biochemistry to characterise the bacterial AAA+ ATPase RavA and the Mitochondrial Complex I Assembly Complex. I moved to the Guettler lab in 2020 to work on the cryo-EM characterisation of tankyrase.
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Katy joined the ICR in October 2023 as a PhD student. She previously completed an MChem at Durham University, where her research focused on novel therapeutics for Alzheimer's disease. At the ICR she is working on a collaborative project with Professor Guettler and Professor Hoelder, developing tankyrase-directed PROTACs as novel scaffolding inhibitors.
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Email: [email protected]
Location: Chelsea
I completed my B.Tech in Chemical Engineering from Anna University in Chennai, India, in 2013. Following my interest in sustainable bioenergy, I pursued an MRes in Sustainable Bioenergy at the School of Biosciences, University of Nottingham, UK, from 2014 to 2016. During my time there, I had the opportunity to intern at the Flow Cytometry Facility based in Queens Medical Centre in Nottingham, which inspired me to pursue higher research studies in basic science. Motivated by my newfound passion, I embarked on a PhD in the prestigious Max Planck Research Group, based at the Malopolska Centre of Biotechnology in Krakow, Poland. My doctoral research focussed on unravelling the mysteries of an ancient ubiquitin-like protein (Urm1) conjugation mechanism called urmylation. To investigate its function, I employed crystallography, mass spectrometry, and biochemical assays, successfully deciphering the intricate workings of urmylation. In May 2023, I joined the Guettler lab to study the molecular mechanisms of the Wnt/β-catenin signalling pathway.
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Email: [email protected]
Location: Sutton
During my bachelor's degree at Erasmus University College, I completed a summer internship at Karolinska Institute in the field of cancer biology. I continued with my studies at Imperial College London in Molecular Basis of Human Disease. Here at the ICR, I am studying the molecular mechanisms of Wnt/beta-catenin signalling.
Professor Sebastian Guettler's group have written 28 publications
Most recent new publication 9/2024
See all their publicationsResearch, projects and publications in this group
ADP-ribosylation is a post-translational modification carried out by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. ADP-ribosylation controls many aspects of cell function, including DNA repair, cell division, telomere maintenance, chromatin dynamics, apoptosis and various signal transduction processes. Given their roles in DNA repair, telomere homeostasis and cancer-relevant signalling pathways, several ARTs are being explored as potential cancer therapy targets.
In humans, the family of intracellular ARTs encompasses 17 members with similar catalytic domains but greatly diverse non-catalytic accessory domains. Different catalytically active ARTs can either transfer a single unit of ADP-ribose or attach ADP-ribose processively, thereby constructing poly(ADP-ribose) (PAR) chains, which can be of varying length and structure. Enzymes in the latter group are known as poly(ADP-ribose)polymerases (PARPs). Compared to other types of post-translational modification, such as phosphorylation, PARylation remains understudied.
We take a particular interest in the PARP enzyme tankyrase, which fulfils a wide range of biological functions, many of which are relevant to cancer. The human genome encodes two highly similar tankyrase paralogues, TNKS and TNKS2. Both share a C-terminal catalytic PARP domain, a set of five N-terminal ankyrin repeat clusters (ARCs) responsible for substrate recruitment, and a polymerising sterile alpha motif (SAM) domain in between.
Our previous structure-function work has revealed the mechanisms of substrate recognition and polymerisation by tankyrase and shown that tankyrase can act as a scaffolding protein, independently of its catalytic function. We now aim to use both X-ray crystallography and cryo-electron microscopy to understand how tankyrase’s various domains act together. Moreover, we work with chemists to develop novel approaches to modulate tankyrase function.
Tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to recruit binding partners, many of which are also PARylated by tankyrase’s PARP domain. ARCs recognise degenerate peptide motifs found in many proteins. Our earlier work (Guettler et al., 2011) has revealed the substrate recognition mechanism and explained how the rare human disease Cherubism is caused. The sterile alpha motif (SAM) domain enables tankyrase polymerisation. We have revealed the mechanism of tankyrase polymerisation and shown that both ARCs and the SAM domain polymer fulfil essential scaffolding roles and are required for efficient substrate modification (Mariotti et al., 2016). (Images modified from Guettler et al., 2011; Mariotti et al., 2016 and Pollock et al., 2017)
Molecular mechanisms of Wnt/beta-catenin signalling, telomere maintenance and their regulation by poly(ADP-ribosyl)ation
In a series of projects, we take a reductionist approach to study how large macromolecular complexes coordinate Wnt/beta-catenin signalling and telomere length homeostasis and how they are controlled by tankyrase-dependent poly(ADP-ribosyl)ation. We combine biochemical assays with cryo-electron microscopy and X-ray crystallography to uncover the detailed mechanisms governing the functions of these complexes and their regulation.
Besides uncovering fundamental mechanisms underlying stem and cancer cell function, we endeavour to understand the molecular basis of disease mutations and open up new opportunities for pharmacological intervention.
Wnt/beta-catenin signalling revolves around controlling the levels of the transcriptional co-activator beta-catenin. A multi-protein beta-catenin destruction complex captures cytoplasmic beta-catenin and limits its abundance by initiating its phosphorylation- and ubiquitination-dependent degradation. Notably, destruction complex function is impaired in the vast majority of colorectal cancer cases. Wnt stimulation remodels the destruction complex into a membrane-localised “Wnt signalosome” incapable of destabilising beta-catenin. Tankyrase controls the receptiveness of cells to incoming Wnt signals by PARylating AXIN, thereby destabilising the destruction complex or promoting Wnt signalosome formation. (Images modified from Mariotti et al., 2017)
A small number of key signalling pathways collaborate to confer stem-cell properties to cells, and the Wnt/beta-catenin pathway is a prototypic example for such a pathway. Wnt/beta-catenin signalling plays important roles in embryonic development and adult organ homeostasis. It is dysregulated in a number of different cancer types, most prominently in colorectal cancers, the vast majority of which bear mutations in components of the pathway.
At the same time, stem and most cancer cells rely on active telomerase to prevent erosion of their telomeres and maintain their unlimited replicative potential. Recent findings show that Wnt/beta-catenin signalling and telomere homeostasis are closely intertwined at multiple levels and form an integrated self-renewal programme, relevant to normal tissue regeneration, ageing and cancer.
The poly(ADP-ribose)polymerase (PARP) tankyrase both promotes Wnt/beta-catenin signalling and is essential for normal telomere extension in humans, thereby providing an important link between both processes.
Our overarching goal is to understand the precise molecular mechanisms that underlie Wnt/beta-catenin signalling, telomere maintenance and their control by poly(ADP-ribosyl)ation. We have a long-standing interest in deciphering the structural basis and molecular mechanisms of tankyrase function.
We employ biochemistry, structural biology and cell biology to study the molecular mechanisms of Wnt/beta-catenin signalling and telomere homeostasis, with a particular focus on how poly(ADP-ribosyl)ation (PARylation) controls both processes. Besides understanding fundamental mechanisms of cell function, we aim to uncover novel potential therapeutic avenues in cancer.
We take a multidisciplinary approach to study Wnt/beta-catenin signalling, telomere maintenance and their regulation by poly(ADP-ribosyl)ation. Structural biology is at the centre of our work. (Images modified from Mariotti et al., 2016)
Vacancies at the ICR
Working at the ICR
Postdoctoral Training Fellow - Endocrine Control Mechanisms
Under the guidance of Professor Cathrin Brisken, we are seeking a highly motivated and ambitious Postdoctoral Training Fellow to combine innovative patient-derived xenograft models and genetic tools to disentangle the role of estrogen and progesterone receptor signaling in breast cancer. The work contributes to gaining more insights into patient-specific hormone dependencies and factors determining them with the aim of personalizing breast cancer therapy and prevention. The successful candidate will be part of a transdisciplinary team of biologists, clinicians and computational scientists and part of close interactions with groups at the ICR, the RMH and King’s College as well Prof. Brisken’s research group at EPFL, Switzerland. About you The successful candidate must have a PhD in biochemistry, pharmacology, cell or molecular biology and demonstrable experience in planning and designing experiments. Ability to write efficient computer code would is desirable. Candidates who are nearing completion of their PhD may apply, but confirmation on awarded PhD is required within 6 months of employment. The ICR has a workforce agreement stating that Postdoctoral Training Fellows can only be employed for up to 7 years as a PTDF at the ICR ( this includes experience gained at PDTF level prior to joining the ICR). For general information on Postdocs at The ICR, more information can be found here. Research Group Information Under the leadership of Professor Cathrin Brisken, The Endocrine Control Mechanisms group are using intraductal mammary gland implantation, and ex vivo studies using breast cancers expanded via intraductal implantation. We also use transcriptomic and proteomic studies to investigate therapeutics for breast cancer patients and improve the development of novel treatment options for them. Directorate Information The Breast Cancer Now Toby Robins Research Centre, within the Division of Breast Cancer Research of the Institute of Cancer Research which is the first centre in the UK entirely devoted to breast cancer research. Our goal is to advance research into the causes, diagnosis and treatment of breast cancer. It is located in state-of-the-art laboratory space, with excellent core facilities and is funded through a long term renewable programme grant from Breast Cancer Now. The Centre is Directed by Clinician Scientist Professor Andrew Tutt, Professor Chris Lord is Deputy Director of the Centre. What we offer A dynamic and supportive research environment Access to state-of-the-art facilities and professional development opportunities Collaboration with leading researchers in the field Competitive salary and pension We encourage all applicants to access the job pack attached for more detailed information regarding this role.
Postdoctoral Training Fellow
Under the leadership of Claudio Alfieri, we are seeking to appoint a Postdoctoral Training Fellow to join the Molecular Mechanisms of Cell Cycle Regulation Group at the Chester Beatty Laboratories, Fulham Road in London. This project aims to investigate the molecular mechanisms of cell cycle regulation by macromolecular complexes involved in cell proliferation decisions, by combining genome engineering, proteomics and in situ structural biology. For general information on Post Doc's at The ICR can be found here. Key Requirements The successful candidate must have a PhD in cellular biochemistry and experience in Cryo-EM and CLEM is desirable. The ICR has a workforce agreement stating that Postdoctoral Training Fellows can only be employed for up to 7 years as PDTF at the ICR, providing total postdoctoral experience (including previous employment at this level elsewhere) does not exceed 7 years Department/Directorate Information: The candidate will work in the Molecular Mechanisms of Cell Cycle Regulation Group within the ICR Division of Structural Biology headed by Prof. Laurence Pearl and Prof. Sebastian Guettler. The division has state-of-the-art facilities for protein expression and biophysics/x-ray crystallography, in particular the Electron Microscopy Facility is equipped with a Glacios 200kV with Falcon 4i detector with Selectris energy filter and the ICR has access to Krios microscopes via eBIC and the LonCEM consortium. We encourage all applicants to access the job pack attached for more detailed information regarding this role. For an informal discussion regarding the role, please contact Claudio Alfieri via Email on [email protected]
Employee Story
Dr Federico Tidu is a Postdoctoral Training Fellow in Dr Christian Zierhut’s Cancer Biology – Genome Stability and Innate Immunity Team. He and his team are based in our Chester Beatty Laboratories building in Chelsea, Central London.
"Working in Chelsea is great and there’s a very good community here."
Industrial partnership opportunities with this group
Opportunity: Biomarker for CDK4/6 and/or aromatase inhibitor response in breast cancers
Commissioner: Dr Maggie Cheang
Recent discoveries from this group
