Oxidative damage, inflammation, genotoxic effect, and global DNA methylation caused by inhalation of formaldehyde and the purpose of melatonin

Bernardini, Letícia; Barbosa, Eduardo José; Charão, Mariele Feiffer; Göethel, Gabriela; Müller, Diana; Bau, Claiton H.D.; Steffens, Nadine Arnold; Stein, Carolina dos Santos; Moresco, Rafael Noal; García, Solange Cristina; Vencato, Marina S.; Brucker, Natália

doi:10.1093/toxres/tfaa079

Cited by 15 publications

(6 citation statements)

References 85 publications

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“…3A). To test this hypothesis, we first examined whether FA induces base damage, as oxidative lesions can be converted to 5’-flaps by the BER pathway 41 . Accordingly, we observed that FA elevated cellular levels of 8-oxo-deoxyguanine (8-OXO-dG) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Flap endonuclease 1 repairs DNA-protein crosslinks via ADP-ribosylation

Sun,

Jenkins,

El Touny

et al. 2023

Preprint

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DNA-protein crosslinks (DPCs) are among the most ubiquitous and detrimental DNA lesions which arise from exposure to metabolic stresses, drugs, or crosslinking agents such as formaldehyde (FA). FA is a cellular by-product of methanol metabolism, histone demethylation, lipid peroxidation as well as environmental pollutants. Failure to repair FA-induced DPCs blocks nearly all chromatin-based processes including replication and transcription, leading to immunodeficiencies, neurodegeneration, and cancer. Yet, it remains largely unknown how the cell repairs DPCs. The study of DPC repair is impeded by our incomprehension of the types of proteins crosslinked by FA due to the lack of techniques to identify the DPCs. Here, we designed a novel bioassay to profile FA-induced DPCs by coupling cesium chloride differential ultracentrifugation with HPLC-mass spectrometry (MS). Using the method, we revealed the proteome of FA-induced DPCs in human cells and found that the most abundant proteins that form DPCs are PARP1, topoisomerases I and II, methyltransferases, DNA and RNA polymerases, histones, as well as ribosomal proteins. To identify enzymes that repair DPCs, we carried out RNA interference screening and found that downregulation of flap endonuclease 1 (FEN1) rendered cells hypersensitive to FA. Since FEN1 possesses 5'-flap endonuclease activity, we hypothesized that FA induces DPC-conjugated 5'-flap DNA fragments that can be processed by FEN1. Indeed, we demonstrate that FA damages DNA bases that are converted into 5'-flap via the base excision pathway (BER). We also observed that the damaged DNA bases were colocalized with DPCs and FEN1. Mechanistically, we showed that FEN1 repairs FA-induced DPCs in vivo and cleaves 5'-flap DNA substrate harboring DPC mimetic in vitro. We also found that FEN1 repairs enzymatic topoisomerase II (TOP2)-DPCs induced by their inhibitors etoposide and doxorubicin independently of the BER pathway, and that FEN1 and the DPC-targeting protease SPRTN act as parallel pathways for the repair of both FA-induced non-enzymatic DPCs and etoposide-induced enzymatic TOP2-DPCs. Notably, we found that FA-induced non-enzymatic DPCs and enzymatic TOP2-DPCs are promptly modified by poly-ADP-ribosylation (PARylation), a post-translational modification catalyzed by PARP1, a key DNA damage response effector that acts by PARylating both DNA damage sites and DNA repair proteins. We performed immunoprecipitation (IP) assays with anti-PAR antibody for HPLC-MS and identified FEN1 as a PARylation substrate. Next, we showed that PARylation of DPC substrates signaled FEN1 whereas PARylation of FEN1 drove FEN1 to DPC sites. Finally, using the enzymatic labeling of the terminal ADP-ribose-MS method, we identified the E285 residue of FEN1 as a dominant PARylation site, which appeared to be required for FEN1 relocation to DPCs. Taken together, our work not only unveiled the identities of FA-induced DPCs but also discovered an unprecedented PARP1-FEN1 nuclease pathway as a universal and imperative mechanism to repair the miscellaneous DPCs and prevent DPC-induced genomic instability.

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Section: Resultsmentioning

confidence: 99%

Flap endonuclease 1 repairs DNA-protein crosslinks via ADP-ribosylation

Sun,

Jenkins,

El Touny

et al. 2023

Preprint

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“…Notably, melatonin also alleviated oxidative damage of lipids and DNA in primate liver [153] and peripheral blood lymphocytes of healthy, non-smoking males [154]. Additionally, in vitro and in vivo settings have illuminated the broad potential of melatonin to address the genotoxicity of stressors such as arecoline [155], lead ( [156]), formaldehyde [157], the endocrine-disrupting bisphenol A [158] or engineered titanium dioxide nanoparticles [159].…”

Section: Role Of Melatonin In Counteracting Sulfur and Nitrogen Musta...mentioning

confidence: 99%

Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics

et al. 2023

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Sulfur and nitrogen mustards, bis(2-chloroethyl)sulfide and tertiary bis(2-chloroethyl) amines, respectively, are vesicant warfare agents with alkylating activity. Moreover, oxidative/nitrosative stress, inflammatory response induction, metalloproteinases activation, DNA damage or calcium disruption are some of the toxicological mechanisms of sulfur and nitrogen mustard-induced injury that affects the cell integrity and function. In this review, we not only propose melatonin as a therapeutic option in order to counteract and modulate several pathways involved in physiopathological mechanisms activated after exposure to mustards, but also for the first time, we predict whether metabolites of melatonin, cyclic-3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and N1-acetyl-5-methoxykynuramine could be capable of exerting a scavenger action and neutralize the toxic damage induced by these blister agents. NLRP3 inflammasome is activated in response to a wide variety of infectious stimuli or cellular stressors, however, although the precise mechanisms leading to activation are not known, mustards are postulated as activators. In this regard, melatonin, through its anti-inflammatory action and NLRP3 inflammasome modulation could exert a protective effect in the pathophysiology and management of sulfur and nitrogen mustard-induced injury. The ability of melatonin to attenuate sulfur and nitrogen mustard-induced toxicity and its high safety profile make melatonin a suitable molecule to be a part of medical countermeasures against blister agents poisoning in the near future.

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“…FA is a potent mutagen that causes DNA strand breakage, DNA–protein crosslink breakage and oxidative damage to DNA bases. Bernardini et al (2020) used the comet test and MN assay to measure genetic damage in an in vitro experiment involving rat bone marrow mesenchymal stem cells. The comet test revealed a dose‐dependent increase in induced DNA strand breakage.…”

Section: Endogenous Fa In Pathological Statesmentioning

confidence: 99%

Dual effects of endogenous formaldehyde on the organism and drugs for its removal

Chen,

Zhang

et al. 2023

J of Applied Toxicology

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Endogenous formaldehyde (FA) is produced in the human body via various mechanisms to preserve healthy energy metabolism and safeguard the organism. However, endogenous FA can have several negative effects on the body through epigenetic alterations, including cancer growth promotion; neuronal, hippocampal and endothelial damages; atherosclerosis acceleration; haemopoietic stem cell destruction and haemopoietic cell production reduction. Certain medications with antioxidant effects, such as glutathione, vitamin E, resveratrol, alpha lipoic acid and polyphenols, lessen the detrimental effects of endogenous FA by reducing oxidative stress, directly scavenging endogenous FA or promoting its degradation. This study offers fresh perspectives for managing illnesses associated with endogenous FA exposure.

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Oxidative damage, inflammation, genotoxic effect, and global DNA methylation caused by inhalation of formaldehyde and the purpose of melatonin

Cited by 15 publications

References 85 publications

Flap endonuclease 1 repairs DNA-protein crosslinks via ADP-ribosylation

Flap endonuclease 1 repairs DNA-protein crosslinks via ADP-ribosylation

Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics

Dual effects of endogenous formaldehyde on the organism and drugs for its removal

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