Detailed information about our projects:
My research focuses on the cytoplasmic iron-sulfur protein assembly (CIA complex), required for delivering the iron-sulfur (Fe-S) clusters into target proteins. Fe-S clusters are small inorganic cofactors found in hundreds of proteins and are required in virtually all organisms from bacteria to humans. Recent studies have shown that the CIA-machinery targets Fe-S clusters to several apoproteins involved in DNA-metabolism. The co-localization of the CIA complex on components of the mitotic machinery suggests that mitotic proteins are Fe-S proteins. In my project we have identified for the first time a mitotic Fe-S protein, which plays a direct role in the mitotic pathway. We currently aim to determine the role played by Fe-S clusters in the activity of this protein.
Protein-protein interactions (PPIs) are of central importance for many areas of biological research. One important challenge in biology is to understand how protein complexes respond to genetic perturbations. In my projects, I work on developing high-throughput genetic screens that can be used to systematically identify genes important for the physical interaction between protein pairs. I validate our new approaches by screening for mutants that affect the interaction between selected protein pairs with roles in genome stability. The identification of such mutants proves to be valuable for unraveling important regulatory mechanisms, which regulate the assembly of these complexes.
Fe-S clusters are small inorganic cofactors found in hundreds of proteins and are required in virtually all organisms from bacteria to humans. Biogenesis of the latter proteins additionally requires the cytoplasmic iron-sulfur protein assembly (CIA) machinery. Recent studies have shown that the CIA-machinery targets Fe-S clusters to several apoproteins involved in DNA-metabolism. Still, currently it is unclear whether the interaction between the CIA complex occurs in the cytoplasm, or at the specific site of activity of the targeted apo-proteins. The aim of my project is to determine if the interaction between the CIA targeting complex and specific client proteins, and the delivery of the Fe-S cluster occurs in the cytoplasm, or at their specific site of activity (e.g., at the nuclear DNA). I am also interested in identifying the proteins that mediate this crucial step.
Lee Peters and Ofri Karmon
Ubiquitin-mediated proteasomal degradation of many proteins plays a key role in protein quality control (PQC). Still, the proteasome itself can become dysfunctional as a result of transcriptional and translational failures, genomic mutations, or diverse stress conditions, which can lead to misfolded proteins in every compartment of the cell. In this case, the regulatory pathways, the identity of the cellular machinery that mediates the sorting sequestration, and elimination of misfolded proteasomal subunits are still not well understood. Our work focuses on gaining mechanistic insight into the formation of proteasome aggregates that form as a result of misassembled proteasome, or in cases of cell starvation, with the ultimate goal to understand their role, and whether they represent similar or different aggregates.
Protein ubiquitination has been linked to the DNA damage response (DDR), but the role of the reversal process has not yet been characterized. In my project I'm interested in identifying the overall effect of DUBs in DDR. Specifically, I am asking whether the mono-ubiquitin, which was previously shown to modify histone H2B upon the induction of DNA damage, must be removed by certain DUBs in order to allow proper DDR.
Marina Volpe and Roy Avraham
The ubiquitin proteasome system (UPS) marks myriad proteins for degradation. Recently, we performed a genetic screen in yeast for proteins with roles in genome stability that is regulated by the UPS. One of the candidates was Apc11, the RING catalytic core of the anaphase promoting complex/cyclosome (APC/C), an E3-ligase that acts as a master regulator of the cell cycle. In our project we try to gain further mechanistic insight into the degradation of Apc11 by the UPS. Furthermore, we want to figure out why cells have a degradation mechanism for the catalytic subunit of the APC/C, and the role of this process in keeping the genome stable.