RRC ID 76023
Author Nicolai MM, Weishaupt AK, Baesler J, Brinkmann V, Wellenberg A, Winkelbeiner N, Gremme A, Aschner M, Fritz G, Schwerdtle T, Bornhorst J.
Title Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans.
Journal Int J Mol Sci
Abstract Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, nor the possibly resulting toxicity are characterized yet. In this study, we use the model organism Caenorhabditis elegans to investigate the mode of action of Mn toxicity, focusing on genomic integrity by means of DNA damage and DNA damage response. Experiments were conducted to analyze Mn bioavailability, lethality, and induction of DNA damage. Different deletion mutant strains were then used to investigate the role of base excision repair (BER) and dePARylation (DNA damage response) proteins in Mn-induced toxicity. The results indicate a dose- and time-dependent uptake of Mn, resulting in increased lethality. Excessive exposure to Mn decreases genomic integrity and activates BER. Altogether, this study characterizes the consequences of Mn exposure on genomic integrity and therefore broadens the molecular understanding of pathways underlying Mn-induced toxicity. Additionally, studying the basal poly(ADP-ribosylation) (PARylation) of worms lacking poly(ADP-ribose) glycohydrolase (PARG) parg-1 or parg-2 (two orthologue of PARG), indicates that parg-1 accounts for most of the glycohydrolase activity in worms.
Volume 22(20)
Published 2021-10-9
DOI 10.3390/ijms222010905
PII ijms222010905
PMID 34681565
PMC PMC8535284
MeSH Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development* Caenorhabditis elegans Proteins / genetics DNA Damage* DNA Repair Dose-Response Relationship, Drug GTPase-Activating Proteins / genetics* Manganese / toxicity* Models, Animal Mortality Oxidative Stress / drug effects Poly(ADP-ribose) Polymerases / genetics Time Factors
C.elegans tm4374 tm6691 tm2862