Forscherdatenbank

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Prof. Dr. Ivan Dikic

Frankfurt/Mainz
Charité - Universitätsmedizin Berlin

University Hospital Frankfurt Institute of Biochemistry II (IBC2)

Theodor-Stern-Kai 7

60590 Frankfurt am Main

Programme

Exploitation of Oncogenic Mechanisms (EOM)

Molecularly Targeted Therapy (MTT)

Übersicht

Research within the Dikic group is dedicated to deciphering the molecular mechanisms underlying cellular signalling pathways. A major focus is on how ubiquitin controls multiple cellular processes which have a high relevance to human diseases such as cancer, neurodegenerative disorders and inflammation.
Ubiquitin signals are recognized by specific ubiquitin-binding domains (UBDs) in receptor proteins, several of which are e.g. implicated in DNA replication and repair. Previous work within the group identified UBDs that play critical roles in recruitment of translesion synthesis polymerases to ubiquitinated PCNA, thus controlling the post-replicative DNA damage response.
One novel UBD was identified in a protein called SPRTN (SprT-like domain at the N-terminus). In a large collaborative effort, we have identified biallelic germline mutations in the corresponding gene in three patients from two unrelated families who were presenting with early onset hepatocellular carcinoma (HCC) in addition to a segmental progeroid phenotype.
More recently, the group discovered a role for SPRTN as a DNA-dependent protease and identified SPRTN as the first mammalian protease responsible for resolving DNA-protein crosslinks (DPCs). DPCs, if not resolved, become physical impediments to essential processes like DNA replication and gene transcription. Cells derived from patients with a segmental progeria/Rujis-Aalfs syndrome are defective in the removal of DPCs and are highly susceptible to cell death when exposed to DPC-inducing drugs, e.g. those employed in chemotherapy. We are now investigating the role of SPRTN metalloprotease domain further both by biochemical and structural approaches and functional studies in mouse models to better understand how SPRTN contributes to genome maintenance and prevents accelerated aging and tumorigenesis.