<scp>DNA–protein</scp> crosslinks from environmental exposure: Mechanisms of formation and repair

Kojima, Yoshitane; Machida, Yuichi

doi:10.1002/em.22381

Cited by 22 publications

(17 citation statements)

References 117 publications

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“…When external factors induce DNA damage, the cells can mobilize corresponding repair mechanisms to reverse these damages in order to maintain genetic stability. The nucleotide excision repair (NER) pathway, the major mechanism in the process of DNA repair, primarily eliminates bulky adducts arising from exposure to environmental agents [30][31][32]. Xeroderma pigmentosum group A (XPA) and xeroderma pigmentosum group C (XPC) are the initial recognizing proteins responsible for the recruitment of relevant repair apparatus to the DNA damage [33][34][35].…”

Section: Discussionmentioning

confidence: 99%

Astragalus polysaccharide protects formaldehyde-induced toxicity by promoting NER pathway in bone marrow mesenchymal stem cells

She

Zhao

et al. 2021

Folia Histochem Cytobiol.

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Introduction. In our previous study, it has been confirmed that formaldehyde (FA) not only inhibits the proliferative activity, but also causes DNA-protein crosslinks (DPCs) formation in bone marrow mesenchymal stem cells (BMSCs). The purpose of this study was to detect the protective effect of astragalus polysaccharide (APS) against the cytotoxicity and genotoxicity of BMSCs exposed to FA, and to explore potential molecular mechanisms of APS activity.Material and methods. Human BMSCs were cultured in vitro and randomly divided into control cells (Ctrl group), FA-treated cells (FA group, 120 μmol/L), and cells incubated with FA and increasing concentrations (40, 100, or 400 μg/mL) of APS (FA + APS groups). Cytotoxicity was measured by MTT assay. DNA strand breakage, DNA-protein crosslinks (DPCs), and micronucleus formation were respectively detected by comet assay, KCl-SDS precipitation assay, and micronucleus assay. The mRNA and protein expression level of xeroderma pigmentosum group A (XPA),xeroderma pigmentosum group C (XPC), excision repair cross-complementation group 1 (ERCC1), replication protein A1 (RPA1), and replication protein A2 (RPA2) were all detected by qRT-PCR and Western Blot.Results. Compared with the FA group, the cytotoxicity, DNA strand breakage, DPCs, and micronucleus levels were decreased significantly in FA + APS groups (P < 0.01). Meanwhile, the mRNA and protein expression of XPA, XPC, ERCC1, RPA1, and RPA2 were up-regulated significantly in the FA + APS groups (P < 0.05) with the most prominent effect of the 100 μg/mL APS. Conclusions.Our results suggest that APS can protect the cytotoxicity and genotoxicity of human BMSCs induced by FA. The mechanism may be associated with up-regulated expression of XPA, XPC, ERCC1, RPA1, and RPA2 in the nucleotide excision repair (NER) pathway which promotes DNA damage repair.

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Section: Discussionmentioning

confidence: 99%

Astragalus polysaccharide protects formaldehyde-induced toxicity by promoting NER pathway in bone marrow mesenchymal stem cells

She

Zhao

et al. 2021

Folia Histochem Cytobiol.

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“…It has been shown that SPRTN protease activity is tightly regulated by several mechanisms to prevent uncontrolled proteolysis of proteins not at DPC lesions (Kojima and Machida, 2020;Reinking et al, 2020;Stingele et al, 2017). First, SPRTN undergoes the ubiquitin switch (Stingele et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging

et al. 2020

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DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that threaten genomic integrity. Recent findings highlight that SPRTN, a specialized DNA-dependent metalloprotease, is a central player in proteolytic cleavage of DPCs. Previous studies suggest that SPRTN deubiquitination is important for its chromatin association and activation. However, the regulation and consequences of SPRTN deubiquitination remain unclear.Here we report that, in response to DPC induction, the deubiquitinase VCPIP1/VCIP135 is phosphorylated and activated by ATM/ATR. VCPIP1, in turn, deubiquitinates SPRTN and promotes its chromatin relocalization. Deubiquitination of SPRTN is required for its subsequent acetylation, which promotes SPRTN relocation to the site of chromatin damage. Furthermore, Vcpip1 knockout mice are prone to genomic instability and premature aging. We propose a model where two sequential post-translational modifications (PTMs) regulate SPRTN chromatin accessibility to repair DPCs and maintain genomic stability and a healthy lifespan.

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“…TOP2-DPCs can also be proteolysed by non-proteasomal pathways 245 , 248 , 254 – 256 , and non-proteolytically by TDP2 following their SUMOylation and unfolding by ZNF451 (refs 257 – 259 ) (Fig. 6 ).…”

Section: Topoisomerases and Genome Instabilitymentioning

confidence: 99%

Human topoisomerases and their roles in genome stability and organization

Pommier

Nussenzweig

Takeda

et al. 2022

Nat Rev Mol Cell Biol

229

140

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Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA–protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer.

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DNA–protein crosslinks from environmental exposure: Mechanisms of formation and repair

Cited by 22 publications

References 117 publications

Astragalus polysaccharide protects formaldehyde-induced toxicity by promoting NER pathway in bone marrow mesenchymal stem cells

Astragalus polysaccharide protects formaldehyde-induced toxicity by promoting NER pathway in bone marrow mesenchymal stem cells

Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging

Human topoisomerases and their roles in genome stability and organization

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