Project Details
Projekt
Ubiquilins in DNA repair and neurodegeneration
Applicant
Dr. Ron Jachimowicz
Subject Area
Cell Biology
Toxicology, Laboratory Medicine
Toxicology, Laboratory Medicine
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 496650118
Genotoxic stress activates the DNA damage response (DDR), which leads to repair of DNA through several pathways, including homologous recombination (HR) and non-homologous end-joining (NHEJ). We previously identified UBQLN4 in a genome instability syndrome being a crucial negative regulator of HR. UBQLN4 is part of the Ubiquilin family that comprises 4 members (UBQLN1-4). Ubiquilins are shuttle factors that mediate target recognition by the proteasome. We recently identified UBQLN1 in a further novel genome instability syndrome. Affected individuals display signs of genome instability, including a marked neurodegeneration, similar to what we observed in our UBQLN4 syndrome patients. Unlike Ubiquilin’s yeast orthologue Dsk2, UBQLN1 has been shown to have a role in autophagy-mediated degradation suggesting that this extra role has been acquired during expansion of the Ubiquilin family in higher eukaryotes. Moreover, UBQLN1 and UBQLN4 closely interact to maintain protein homeostasis. In this proposal we aim to explore the causes and consequences of deregulated DNA repair together with the co-applicants of this research consortium to explain important phenotypes observed in our novel human Ubiquilin genome instability syndromes. Importantly, these insights will serve as a blueprint to understand the intricate relationship between the DDR, protein homeostasis and neurodegeneration. In Aim 1, we will systematically examine together with P4 (Hoppe) the functional overlaps and differences between the Ubiquilin family members in the DDR and for protein homeostasis in vitro and in vivo. In Aim 2, we will capitalize on our UBQLN1- and UBQLN4 syndrome patients displaying clinical signs of neurodegeneration. We have thus generated conditional Ubqln1 and Ubqln4 knockout mouse alleles that we will utilize to study the relation of neurodegeneration and dysfunctional DNA repair together with P1 (Hänsel-Hertsch). Together with P3 (Wang/Schumacher) we will validate our findings in the respective C. elegans model. With these models we will have a pre-clinical tool to explore therapeutic options for neurodegeneration based on DDR- and protein homeostasis- deficiencies.
DFG Programme
Research Units
