Resolution of R-loops by topoisomerase III-β (TOP3B) in coordination with the DEAD-box helicase DDX5

Saha, Sourav; Yang, Xi; Huang, Shar-yin N.; Agama, Keli; Baechler, Simone A.; Sun, Yilun; Zhang, Hongliang; Saha, Liton Kumar; Su, Shuaikun; Jenkins, Lisa M. Miller; Wang, Weidong; Pommier, ﻿Yves

doi:10.1016/j.celrep.2022.111067

Cited by 22 publications

(21 citation statements)

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“…Several studies have revealed that various tricyclic and tetracyclic backbone‐based derivatives may extend their antitumor activities through DNA‐intercalating activities and topoisomerase blocking capabilities 11–15 . It has been unveiled that TOP–DNA covalent complexes from either TOP I‐specific poison or TOP II‐specific poison are able to trigger 26S proteasome‐involved degradation indicated as TOP downregulation 16–18 .…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have revealed that various tricyclic and tetracyclic backbone-based derivatives may extend their antitumor activities through DNA-intercalating activities and topoisomerase blocking capabilities. [11][12][13][14][15] It has been unveiled that TOP-DNA covalent complexes from either TOP I-specific poison or TOP II-specific poison are able to trigger 26S proteasome-involved degradation indicated as TOP downregulation. [16][17][18] Our examination demonstrated that WC-A compounds selectively induced the downregulation of both TOP IIα and TOP IIβ in a concentrationdependent manner but had no impact on TOP I protein expression (Figure 2A).…”

Section: Wc-a Derivatives Display Anticancer Activities Through the I...mentioning

confidence: 99%

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Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

et al. 2023

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BackgroundCastration‐resistant prostate cancer (CRPC) is refractory to hormone treatment and the therapeutic options are continuously advancing. This study aims to discover the anti‐CRPC effects and underlying mechanisms of small‐molecule compounds targeting topoisomerase (TOP) II and cellular components of DNA damage repair.MethodsCell proliferation was determined in CRPC PC‐3 and DU‐145 cells using anchorage‐dependent colony formation, sulforhodamine B assay and flow cytometric analysis of CFSE staining. Flow cytometric analyses of propidium iodide staining and JC‐1 staining were used to examine the population of cell‐cycle phases and mitochondrial membrane potential, respectively. Nuclear extraction was performed to detect the nuclear localization of cellular components in DNA repair pathways. Protein expressions were determined using Western blot analysis.ResultsA series of azathioxanthone‐based derivatives were synthesized and examined for bioactivities in which WC‐A13, WC‐A14, WC‐A15, and WC‐A16 displayed potent anti‐CRPC activities in both PC‐3 and DU‐145 cell models. These WC‐A compounds selectively downregulated both TOP IIα and TOP IIβ but not TOP I protein expression. WC‐A13, WC‐A14, and WC‐A15 were more potent than WC‐A16 on TOP II inhibition, mitochondrial dysfunction, and induction of caspase cascades indicating the key role of amine‐containing side chain of the compounds in determining anti‐CRPC activities. Furthermore, WC‐A compounds induced an increase of γH2AX and activated ATR‐Chk1 and ATM‐Chk2 signaling pathways. P21 protein expression was also upregulated by WC‐A compounds in which WC‐A16 showed the least activity. Notably, WC‐A compounds exhibited different regulation on Rad51, a major protein in homologous recombination of DNA in double‐stranded break repair. WC‐A13, WC‐A14, and WC‐A15 inhibited, whereas WC‐A16 induced, the nuclear translocation of Rad51.ConclusionThe data suggest that WC‐A compounds exhibit anti‐CRPC effects through the inhibition of TOP II activities, leading to mitochondrial stress‐involved caspase activation and apoptosis. Moreover, WC‐A13, WC‐A14, and WC‐A15 but not WC‐A16 display inhibitory activities of Rad51‐mediated DNA repair pathway which may increase apoptotic effect of CRPC cells.

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Section: Resultsmentioning

confidence: 99%

Section: Wc-a Derivatives Display Anticancer Activities Through the I...mentioning

confidence: 99%

Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

et al. 2023

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“…) are all DDX5 downstream targets . Literature review of DDX5 studies indicated that DDX5 interacts with multiple topoisomerase (TOP) family proteins including TOP1, TOP2A, TOP2B, and TOP3B to facilitate cancer cell DNA replication and gene transcription. In this regard, the data presented in Figure B indicated that FL118 and the other FL118 derivatives ( FL77-6 , FL77-9, or FL77-24 ) could inhibit TOP1 enzyme activity in nonphysiological high concentrations (100, 50, and 25 μM).…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies revealed that FL118 inhibits DNA repair regulators (e.g., ERCC1 and ERCC6) and induces DNA damage with an unknown mechanism. 13 Recent studies indicated that DDX5 interacts with TOP1, TOP2A, TOP2B, 49 and TOP3B 50 during the DNA transcription−replication process for topological Rloop resolution and DNA repair to avoid cell death by apoptosis. 49,50 Additionally, our recent studies demonstrated that FL118 binds to and then induces the dephosphorylation and degradation of DDX5 protein in both CRC and pancreatic cancer cells, while transiently increasing DDX5 mRNA (due to cell feedback in an attempt to survive).…”

Section: ■ Introductionmentioning

confidence: 99%

“…13 Recent studies indicated that DDX5 interacts with TOP1, TOP2A, TOP2B, 49 and TOP3B 50 during the DNA transcription−replication process for topological Rloop resolution and DNA repair to avoid cell death by apoptosis. 49,50 Additionally, our recent studies demonstrated that FL118 binds to and then induces the dephosphorylation and degradation of DDX5 protein in both CRC and pancreatic cancer cells, while transiently increasing DDX5 mRNA (due to cell feedback in an attempt to survive). 26 Our protein microarray studies further indicated that while FL118 binds to DDX5, FL118 does not bind to DDX1, DDX4, DDX6, DDX10, DDX11, DDX17, DDX18, DDX19B, DDX20, DDX21, DDX25, DDX39, DDX42, DDX43, DDX47, DDX49, DDX54, DDX55, and DDX58 proteins.…”

Section: ■ Introductionmentioning

confidence: 99%

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