As part of an active scientific community that studies the DNA damage response (DDR) and its impact on cancer and aging, research in the lab of Matthias Altmeyer is aimed at elucidating cellular mechanisms of genome integrity maintenance and their deregulation in human disease. Here you can explore who we are and what we do. Welcome!
Reduced operating mode continues due to COVID-19 situation
As the University of Zurich resumes on-site operations with applicable safety concepts in place also our lab resumes experimental work, albeit with reduced capacity and with safety precautions.
In our recent publication in Cell Reports we reveal that the ubiquitin E3 ligase TRIP12, through its PAR-binding WWE domain, targets PARP1 for proteasomal degradation, affecting PARP functions and PARPi efficiency.
We have openings for a postdoctoral researcher and MSc/PhD students to join our lab. If you are interested in cancer biology and genome integrity maintenance and have a liking for quantitative cell biology, please take a look.
Marco’s paper on TRIP12-regulated PARP inhibitor efficiency is out
The ubiquitin ligase TRIP12 limits PARP1 trapping and constrains PARP inhibitor efficiency
We show that the ubiquitin E3 ligase TRIP12, through its PAR-binding WWE domain, targets PARP1 for proteasomal degradation, affecting PARP functions and PARP inhibitor efficiency. Great work with important implications worth following up. Congratulations to Marco Gatti and big thanks to our collaborators Qingyao Huang and Michael Baudis for their help. Published in Cell Reports.
TRIP12 is a PAR-targeted ubiquitin ligase (PTUbL)
The HECT and WWE domains of TRIP12 cooperate to mediate PARP1 turnover
TRIP12 loss sensitizes cancer cells to PARP inhibitors in a PARP1-dependent manner
TRIP12 status may help to estimate how cancer cells respond to PARP inhibition
The DNA damage response factor and chromatin binder 53BP1 generates repair compartments around DNA breaks. In a paper published in EMBO Journal (2019)38:e101379 we show that these nuclear compartments show liquid-like properties, exhibit induced self‐assembly based on 53BP1’s oligomerization potential, and undergo fusion and fission events with potential implications for break clustering and chromosomal translocations. 53BP1 condensates are sensitive to disruption of weak interactions, and can co-assemble and contribute to the activation of tumor suppressor protein p53. See also the News & Views by Piccinno et al.
Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments
DNA repair compartments show liquid‐like properties with droplet fusions and fissions
Phase separation behavior is conferred by 53BP1, and uncoupled from upstream DNA damage detection and γH2AX‐MDC1 accumulation
53BP1 assembly at break sites is abolished by changes in osmotic pressure, temperature, salt concentration, or disruption of hydrophobic interactions
53BP1 optoDroplet experiments indicate multivalency and reveal sequence elements required for clustering
Disruption of 53BP1 phase separation impairs p53 activation and p21 induction upon DNA damage
Replication stress is a hallmark of many cancers. In an article published in the February 2019 issue of Molecular Cell (Volume 73, Issue 4, p641-858) we identify the pre-mRNA cleavage factor WDR33 as regulator of replication stress resilience and demonstrate that, when WDR33 function is impaired, unreleased nascent transcripts and genomic loci re-localize toward the nuclear periphery, where they cause replication stress and DNA damage.
Our paper on PARP inhibitor toxicity is published in Nature Communications! Have a look how high-content imaging reveals the earliest cellular responses to PARP inhibition and unravels the sequence of events from PARP trapping to DNA damage, cell cycle arrest and cell death. Here you can access the complete article and browse through the Editors’ Highlights, or read the UZH/EurekAlert public releases.
Analysis of PARP inhibitor toxicity by multidimensional fluorescence microscopy reveals mechanisms of sensitivity and resistance
Lab research featured in UZH Magazin and in the Annual Report 2017
Research of the group brought to life by Roland Fischer and photographer Marc Latzel for UZH Magazin 01/2018 (UZH News). Download the full article or the complete magazine (in German). Read the English translation here.