DNA Damage Induced by Manganese

Bornhorst, Julia; Schwerdtle, Tanja

doi:10.1039/9781782622383-00604

Cited by 3 publications

(2 citation statements)

References 77 publications

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“…These findings of decreased genomic integrity (increase of DNA strand breaks and oxidatively modified DNA bases) caused by Mn are in line with studies performed in neuroblastoma cells (SH-SY5Y) [57] and further corroborate the results of Yang et al [58], which show that Mn induces increased levels of 8OHdG in the striatum of mice. Other investigations in mammals and (neuronal) cell lines come to the same conclusion [24,41], but studies performed by Sava et al and Oikawa et al suggested that Mn causes an increase of 8oxodG levels of neuronal cells (PK-12), but only if co-incubated with dopamine or melanin [59,60]. Another in vitro study was performed on Mn-toxicity resistant cells (SCOV-3 clones) and showed that these cells have an increased ability of DNA repair, by means of enhanced PARP and AP endonuclease activity compared to the non-resistant original cell line.…”

Section: Mn Causes a Decrease In Genomic Integrity And The Formation Of Oxidative Dna Damage At Sub-toxic And Toxic Concentrationssupporting

confidence: 60%

“…Excessive production of reactive oxygen and nitrogen species (RONS), either directly via a Fenton-like reaction or indirectly by inhibiting the respiratory chain in mitochondria, leads to increased interactions with macromolecules such as DNA [23]. Recent evidence from in vitro studies suggests that Mn may damage the DNA or disturb cellular DNA damage response pathways under conditions of either overload due to high exposure or disturbed homeostasis [24]. The resulting DNA damage in combination with an insufficient DNA repair system might contribute to the neurological dysfunction [25,26].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans

Nicolai

Weishaupt

Baesler

et al. 2021

IJMS

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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.

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Section: Mn Causes a Decrease In Genomic Integrity And The Formation Of Oxidative Dna Damage At Sub-toxic And Toxic Concentrationssupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans

Nicolai

Weishaupt

Baesler

et al. 2021

IJMS

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Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells

Nicolai

Witt

Friese

et al. 2022

Food and Chemical Toxicology

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Divalent and multivalent cations control liquid-like assembly of poly(ADP-ribosyl)ated PARP1 into multimolecular associates in vitro

Sukhanova,

Anarbaev,

Maltseva

et al. 2024

Commun Biol

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The formation of nuclear biomolecular condensates is often associated with local accumulation of proteins at a site of DNA damage. The key role in the formation of DNA repair foci belongs to PARP1, which is a sensor of DNA damage and catalyzes the synthesis of poly(ADP-ribose) attracting repair factors. We show here that biogenic cations such as Mg 2+ , Ca 2+ , Mn 2+ , spermidine 3+ , or spermine 4+ can induce liquid-like assembly of poly(ADP-ribosyl)ated [PARylated] PARP1 into multimolecular associates (hereafter: self-assembly). The self-assembly of PARylated PARP1 affects the level of its automodification and hydrolysis of poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase (PARG). Furthermore, association of PARylated PARP1 with repair proteins strongly stimulates strand displacement DNA synthesis by DNA polymerase β (Pol β) but has no noticeable effect on DNA ligase III activity. Thus, liquid-like self-assembly of PARylated PARP1 may play a critical part in the regulation of i) its own activity, ii) PARG-dependent hydrolysis of poly(ADP-ribose), and iii) Pol β–mediated DNA synthesis. The latter can be considered an additional factor influencing the choice between long-patch and short-patch DNA synthesis during repair.

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DNA Damage Induced by Manganese

Cited by 3 publications

References 77 publications

Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans

Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans

Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells

Divalent and multivalent cations control liquid-like assembly of poly(ADP-ribosyl)ated PARP1 into multimolecular associates in vitro

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