Interplay between symmetric arginine dimethylation and ubiquitylation regulates TDP1 proteostasis for the repair of topoisomerase I-DNA adducts

Bhattacharjee, Sangheeta; Rehman, Ishita; Basu, Saini; Nandy, Souvik; Richardson, Julia M.; Das, Benu Brata

doi:10.1016/j.celrep.2022.110940

Cited by 6 publications

(2 citation statements)

References 56 publications

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“…These results highlighted the behavior of PRMT enzymes in BC and provided evidence for designing different therapeutic strategies targeting PRMT enzymes. PRMT5 regulates arginine symmetrical dimethylation on histone, a critical epigenetic regulator; thus a change in PRMT5 expression has a broad effect on downstream gene expression, in collaboration with another transcriptional regulator [40,41]. Unlike trimethylation on lysine, which usually presents the start of transcription process, the effect of dimethylation is more flexible, including both activation and suppression functions on different histones [42].…”

Section: Discussionmentioning

confidence: 99%

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Liu

Piao

et al. 2022

J Exp Clin Cancer Res

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Background Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candidate drugs are needed. Flavokawain A (FKA), extracted from kava plant, has been recognized as a potential chemotherapy drug in bladder cancer (BC), but its action mechanism remains unclear. Methods We first determined the role of a type II PRMT, PRMT5, in BC tissue samples and performed cytological experiments. We then utilized bioinformatics tools, including computational simulation, virtual screening, molecular docking, and energy analysis, to identify the potential use of PRMT5 inhibitors for BC treatment. In vitro and in vivo co-IP and mutation assays were performed to elucidate the molecular mechanism of PRMT5 inhibitor. Pharmacology experiments like bio-layer interferometry, CETSA, and pull-down assays were further used to provide direct evidence of the complex binding process. Results Among PRMTs, PRMT5 was identified as a therapeutic target for BC. PRMT5 expression in BC was correlated with poor prognosis and manipulating its expression could affect cancer cell growth. Through screening and extensive experimental validation, we recognized that a natural product, FKA, was a small new inhibitor molecule for PRMT5. We noticed that the product could inhibit the action of BC, in vitro and in vivo, by inhibiting PRMT5. We further demonstrated that FKA blocks the symmetric arginine dimethylation of histone H2A and H4 by binding to Y304 and F580 of PRMT5. Conclusions In summary, our research strongly suggests that PRMT5 is a potential epigenetic therapeutic target in bladder cancer, and that FKA can be used as a targeted inhibitor of PRMT5 for the treatment of bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Liu

Piao

et al. 2022

J Exp Clin Cancer Res

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“…The viability of the Leishmania donovani promastigotes was measured by MTT assay. ,,, All EC 50 values were calculated by using the nonlinear variable slope model for finding EC 50 in Prism (ver. 5.0; GraphPad Software, USA).…”

Section: Methodsmentioning

confidence: 99%

Novel Pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline Derivative Selectively Poisons Leishmania donovani Bisubunit Topoisomerase 1 to Inhibit the Antimony-Resistant Leishmania Infection in Vivo

et al. 2023

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The unique bisubunit structure of Leishmania donovani topoisomerase 1B (LdTop1) is a potential drug target in the parasites unlike the monomeric Top1 from its human host counterpart. Here, we report the design, synthesis, and validation of a chimeric pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline derivative (C17) as a novel antileishmanial agent that poisons topoisomerase 1-DNA covalent complexes (LdTop1cc) inside the parasites and inhibits Top1 religation activity both in the drug sensitive and antimony-resistant L. donovani clinical isolates. Importantly, the human Top1 is not sensitive to C17. Further, C17 overcomes the chemical instability of camptothecin (CPT) by generating persistent LdTop1cc-induced DNA breaks inside the parasites even after 12 h of drug removal. Intraperitoneal administration of C17 results in marked reduction of the Leishmania amastigotes from the infected spleen and liver of BALB/c mice. C17 confers a host protective immune-response up-regulating the Th1 cytokines facilitating parasite clearance which can be exploited for treating drug-resistant leishmaniasis.

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Role of UCHL3 in health and disease

Lei,

Xu,

2024

Biochemical and Biophysical Research Communications

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Interplay between symmetric arginine dimethylation and ubiquitylation regulates TDP1 proteostasis for the repair of topoisomerase I-DNA adducts

Cited by 6 publications

References 56 publications

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Novel Pyrido[2′,1′:2,3]imidazo[4,5-c]quinoline Derivative Selectively Poisons Leishmania donovani Bisubunit Topoisomerase 1 to Inhibit the Antimony-Resistant Leishmania Infection in Vivo

Role of UCHL3 in health and disease

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