Nicolas THOMA
Supervisor Project : Molecular basis of thalidomide action
Partner Lab
for fundamental biomedical research aiming at understanding the molecular
mechanisms of health and diseases. FMI specializes in epigenetics of stem cell
development and cell differentiation, mechanisms of cancer, including signalling
pathways and neurobiology. FMI has international recognition as a centre of
excellence in innovative biomedical research. FMI is also dedicated to the training of
graduate students and postdoctoral fellows, affiliated with the University of Basel, where
graduate students are enrolled and where it contributes to the teaching program.
About
The laboratory of Nicolas Thomä (NT) studies the structure of protein complexes
involved in ubiquitination with a focus on DNA repair. Dr. Thomä joined the FMI in
2007, where he is now a senior group-leader. The Thomä lab has trained a number of
PhD student (5) and Postdoctoral fellows (10), many of which have gone on to start their
own labs (DFCI Harvard, Helmholtz Braunschweig), or have leading roles in the
pharmaceutical industry (Novartis, Roche, Glenmark). The laboratory has publications in
the leading journals in the last years and has become interested into how protein function
can be modulated by small molecular weight drugs. The student will be supervised by
NT and Martin Renatus (MR) from Novartis will act as a co-supervisor (H-index 24).
Summary of the Project
Thalidomide (Contergan) was introduced to the European market in 1957 as a sedative. Unfortunately it took more than two years before its teratogenicity was discovered. Thalidomide and its second-generation derivatives (together known as IMiDs) have since been recognized as potent anticancer drugs, and are now widely used in treating multiple myeloma and 5q-dysplasia. The primary cellular target of thalidomide is CRBN (CeRClon) as integrated into the CRL4CRBN complex, an E3 Ub ligase. IMiDs prevent endogenous substrate, such as the transcription factor MEIS2 from binding, and also induce degradation of neo-substrates such as IKZF1/2 and Ck1a. The underlying molecular mechanism is unknown. We will use MS based half-life measurement to identify novel endogenous and neo-substrates, and resolve their mode of binding to CRL4CRB by X-ray crystallography and cryo-EM, as a model for E3 ligases regulation.