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@LabThoma

OUR PROJECTS

We study large protein complexes that maintain genome stability and investigate how they function in the context of chromatin. These studies include DNA damage repair, replication, transcription and telomere architecture. As E3 ubiquitin ligases are involved in many of these processes, we are also interested in how E3 ligases recognise their substrates and study small molecule compounds that divert ligase function.

PROTEIN DEGRADATION

Protein degradation rapidly inactivates protein function and is used in many biological contexts to trigger irreversible transitions. The major protein degradation pathway, the ubiquitin proteasome system (UPS), constitutes hundreds of E3 ubiquitin ligases that attach ubiquitin to thousands of substrates targeting them for proteolytic cleavage by the 26S proteasome. We are interested in how E3 ubiquitin ligases recognize their substrates (Scrima et. al., Cell, 2008), how small molecule compounds such as thalidomide (also known as Contergan or Softenon) divert ligase function to induce degradation of disease-related proteins (Fischer et. al., Nature, 2014 / Petzold et. al., Nature, 2016 / Sievers et. al., Science, 2018) and how the activity of these ligases is regulated by the CSN master regulator (Lingaraju et. al., Nature, 2014 / Cavadini et. al., Nature, 2016).

REGULATION IN CHROMATIN

Genome regulation at the level of transcription, DNA repair and replication, requires highly specific DNA binding by the proteins involved. In eukaryotes, nucleosomes limit DNA access for a substantial part of the genome. This barrier needs to be overcome for DNA repair, or for activation of regulatory regions in transcription. How these DNA binding proteins engage nucleosomal DNA in a sequence-, or DNA damage-dependent manner is an ongoing area of study for the lab using a combination of structural techniques, biochemistry and functional assays. To this end, we have investigated how DDB2 interrogates DNA for the presence of UV-lesions and determined the structure of DDB1-DDB2 in complex with UV damage (Scrima et al., Cell, 2008). We could subsequently show that the DDB2 complex is also able to detect UV-damage in nucleosomes (Fischer et. al., Cell, 2011).

DNA REPLICATION &

DAMAGE REPAIR

Our research centers largely on understanding the mechanism and architecture of the chromosome maintenance machineries. The role of Rif1 protein is known in telomere length maintenance, DNA repair and in DNA replication. We have determined the x-ray crystal structure of yeast Rif1(CTD)-Rap1 complex (Shi at al., Cell, 2013) and Rif1(NTD) bound to DNA overhangs (Mattarocci et al., 2017). Our work revealed the architecture and function of a major component of the telomere-capping complex. We further aim to understand the role of Rif1 in DNA damage repair. Ongoing work is aimed at structurally understanding how Rif1 gets recruited to sites of DNA damage and the role of other effector proteins involved in end protection activity.