Molecular mechanisms of topoisomerase 2 DNA–protein crosslink resolution

Riccio, Amanda A.; Schellenberg, M.J.; Williams, R. Scott

doi:10.1007/s00018-019-03367-z

Cited by 50 publications

(28 citation statements)

References 94 publications

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“…Oxaliplatin-induced DNA-adducts activated nucleotide excision repair through Topoisomerase II, which could attenuate DNA damage and result in oxaliplatin resistance 38 . TOP2A, DNA topoisomerase, is an enzyme that controls and alters the topologic states of DNA during transcription 39 . TOP2A is upregulated and could induce tumor development and progression in multiple tumors 40 – 43 and is proved important therapeutic target of anticancer agents 44 .…”

Section: Discussionmentioning

confidence: 99%

UPF1 promotes chemoresistance to oxaliplatin through regulation of TOP2A activity and maintenance of stemness in colorectal cancer

et al. 2021

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UPF1 is proved to dysregulate in multiple tumors and influence carcinogenesis. However, the role of UPF1 in oxaliplatin resistance in colorectal cancer (CRC) remains unknown. In our study, UPF1 is upregulated in CRC in mRNA and protein levels and overexpression of UPF1 predicts a poor overall survival (OS) and recurrence-free survival (RFS) in CRC patients and is an independent risk factor for recurrence. UPF1 promotes chemoresistance to oxaliplatin in vitro and in vivo. UPF1-induced oxaliplatin resistance can be associated with interaction between zinc finger of UPF1 and Toprim of TOP2A and increasing phosphorylated TOP2A in a SMG1-dependent manner. Moreover, UPF1 maintains stemness in a TOP2A-dependent manner in CRC. Taken together, UPF1 was overexpressed and predicted a poor prognosis in CRC. UPF1 enhanced chemoresistance to oxaliplatin in CRC, which may result from regulation of TOP2A activity and maintenance of stemness. Our findings could provide a new therapy strategy for chemoresistance to oxaliplatin in CRC patients.

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Section: Discussionmentioning

confidence: 99%

UPF1 promotes chemoresistance to oxaliplatin through regulation of TOP2A activity and maintenance of stemness in colorectal cancer

et al. 2021

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“…DNA damage comprises chemical changes to bases and the sugar-phosphate backbone, base loss, single-strand breaks, double-strand breaks (DSBs), and intra- and interstrand crosslinks. Protein-DNA crosslinks arise when topoisomerases are trapped in covalent linkages to DNA by topoisomerase poisons, commonly used in cancer therapy ( Pommier et al, 2006 ; Deweese and Osheroff, 2009 ; Friedberg et al, 2014 ; Thomas and Pommier, 2019 ; Riccio et al, 2020 ). DNA damage detection, signaling and repair systems evolved to manage these threats, termed the DNA damage response (DDR).…”

Section: Introductionmentioning

confidence: 99%

The Safe Path at the Fork: Ensuring Replication-Associated DNA Double-Strand Breaks are Repaired by Homologous Recombination

et al. 2021

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Cells must replicate and segregate their DNA to daughter cells accurately to maintain genome stability and prevent cancer. DNA replication is usually fast and accurate, with intrinsic (proofreading) and extrinsic (mismatch repair) error-correction systems. However, replication forks slow or stop when they encounter DNA lesions, natural pause sites, and difficult-to-replicate sequences, or when cells are treated with DNA polymerase inhibitors or hydroxyurea, which depletes nucleotide pools. These challenges are termed replication stress, to which cells respond by activating DNA damage response signaling pathways that delay cell cycle progression, stimulate repair and replication fork restart, or induce apoptosis. Stressed forks are managed by rescue from adjacent forks, repriming, translesion synthesis, template switching, and fork reversal which produces a single-ended double-strand break (seDSB). Stressed forks also collapse to seDSBs when they encounter single-strand nicks or are cleaved by structure-specific nucleases. Reversed and cleaved forks can be restarted by homologous recombination (HR), but seDSBs pose risks of mis-rejoining by non-homologous end-joining (NHEJ) to other DSBs, causing genome rearrangements. HR requires resection of broken ends to create 3’ single-stranded DNA for RAD51 recombinase loading, and resected ends are refractory to repair by NHEJ. This Mini Review highlights mechanisms that help maintain genome stability by promoting resection of seDSBs and accurate fork restart by HR.

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“…Topoisomerase II inhibitors such as doxorubicin stabilize this complex, which leads to an accumulation of double-stranded breaks as relegation is inhibited. This results in the accumulation of DNA damage, leading to cell death in rapidly dividing cells [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Doxorubicin Delivery by Nitrogen-Doped Graphene Quantum Dots on Cancer Cell Growth: Experimental Study and Mathematical Modeling

et al. 2021

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With 18 million new cases diagnosed each year worldwide, cancer strongly impacts both science and society. Current models of cancer cell growth and therapeutic efficacy in vitro are time-dependent and often do not consider the Emax value (the maximum reduction in the growth rate), leading to inconsistencies in the obtained IC50 (concentration of the drug at half maximum effect). In this work, we introduce a new dual experimental/modeling approach to model HeLa and MCF-7 cancer cell growth and assess the efficacy of doxorubicin chemotherapeutics, whether alone or delivered by novel nitrogen-doped graphene quantum dots (N-GQDs). These biocompatible/biodegradable nanoparticles were used for the first time in this work for the delivery and fluorescence tracking of doxorubicin, ultimately decreasing its IC50 by over 1.5 and allowing for the use of up to 10 times lower doses of the drug to achieve the same therapeutic effect. Based on the experimental in vitro studies with nanomaterial-delivered chemotherapy, we also developed a method of cancer cell growth modeling that (1) includes an Emax value, which is often not characterized, and (2), most importantly, is measurement time-independent. This will allow for the more consistent assessment of the efficiency of anti-cancer drugs and nanomaterial-delivered formulations, as well as efficacy improvements of nanomaterial delivery.

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Molecular mechanisms of topoisomerase 2 DNA–protein crosslink resolution

Cited by 50 publications

References 94 publications

UPF1 promotes chemoresistance to oxaliplatin through regulation of TOP2A activity and maintenance of stemness in colorectal cancer

UPF1 promotes chemoresistance to oxaliplatin through regulation of TOP2A activity and maintenance of stemness in colorectal cancer

The Safe Path at the Fork: Ensuring Replication-Associated DNA Double-Strand Breaks are Repaired by Homologous Recombination

Effects of Doxorubicin Delivery by Nitrogen-Doped Graphene Quantum Dots on Cancer Cell Growth: Experimental Study and Mathematical Modeling

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