Project Details
Projekt
Mechanisms of organismal proteostasis regulation triggered by genotoxic stress
Applicant
Professor Dr. Björn Schumacher
Subject Area
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 531902955
Proteostasis is essential for the functioning of an organism. It has become increasingly evident that the loss of proteostasis during aging is linked to the age-dependent accumulation of DNA damage. DNA damage is constantly inflicted by endogenous and exogenous genotoxic influences and requires highly effective DNA repair mechanisms. Defects in nucleotide excision repair (NER) can give rise to progeroid syndromes that are characterized by accelerated aging and age-dependent diseases occurring already during childhood. Based on our published and preliminary data, we hypothesize that proteostasis plays a major role in the pathological outcomes of DNA damage in the organism. Our overarching aim is, therefore, to better understand how the DNA damage response (DDR) impacts on the network of the proteostasis mechanisms in the organism. In our previous work, we discovered Germline DNA damage-induced systemic stress resistance (GDISR) that is mediated by systemic activation of the ubiquitin proteasome system (UPS). In our recent work, we identified neuronal signaling mechanisms that regulate the organism’s UPS and the unfolded protein response in the endoplasmic reticulum (UPRER) to alleviate toxic protein aggregation. We further showed that neuronal Acetylcholine (ACh) signaling mediates the systemic UPS and UPRER activation. In our preliminary results, we found that ACh signaling also mediates a systemic response to neuronal DNA damage. Moreover, our data have identified the transcription factor HLH-30 as regulator of the UPS in the DNA damage response. We found that HLH-30 is essential for the organism’s survival of persistent DNA damage. Here, we build upon our recent published and unpublished work to establish how the DDR regulates systemic proteostasis. Specifically, we propose to employ the C. elegans system as an experimental model to shed light on how the systemic proteostasis system is regulated by neuronal ACh signaling. We will pursue three specific aims to (Aim 1) define how ACh signaling regulates the systemic activity of the proteostatic network amid DNA damage, (Aim 2) investigate how HLH-30 regulates ACh-mediated effects on organismal proteostasis and protects from the consequences of persistent DNA damage, and (Aim 3) assess the phenotypic consequences of ACh-controlled proteostasis. We propose that defining systemic proteostasis regulators will impact our understanding of organismal health amid DNA damage accumulation during aging and might provide insight into systemic progeroid pathologies in patients suffering from DNA repair deficiencies.
DFG Programme
Research Units
