Regulation of topoisomerase II stability and activity by ubiquitination and SUMOylation: clinical implications for cancer chemotherapy

Ma, Ying; North, Brian J.; Shu, Jianfeng

doi:10.1007/s11033-021-06665-7

Cited by 17 publications

(12 citation statements)

References 94 publications

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“…Since many UIM-containing proteins can participate in ubiquitylation [ 19 ], we assume that ZATT may also have functions in ubiquitin metabolism. It was reported that the ubiquitin–proteasome system is primarily responsible for regulating the stability and activity of TOP2 [ 20 ]. TOP2 is ubiquitinated and degraded by proteasome upon ETO treatment and this process may occur prior to TOPcc removal by TDP2 [ 10 ].…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway

Park

Zhang

Nie

et al. 2023

IJMS

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Etoposide (ETO) is an anticancer drug that targets topoisomerase II (TOP2). It stabilizes a normally transient TOP2–DNA covalent complex (TOP2cc), thus leading to DNA double-strand breaks (DSBs). Tyrosyl-DNA phosphodiesterases two (TDP2) is directly involved in the repair of TOP2cc by removing phosphotyrosyl peptides from 5′-termini of DSBs. Recent studies suggest that additional factors are required for TOP2cc repair, which include the proteasome and the zinc finger protein associated with TDP2 and TOP2, named ZATT. ZATT may alter the conformation of TOP2cc in a way that renders the accessibility of TDP2 for TOP2cc removal. In this study, our genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens revealed that ZATT also has a TDP2-independent role in promoting cell survival following ETO treatment. ZATT KO cells showed relatively higher ETO sensitivity than TDP2-KO cells, and ZATT/TDP2 DKO cells displayed additive hypersensitivity to ETO treatment. The study using a series of deletion mutants of ZATT determined that the N-terminal 1–168 residues of ZATT are required for interaction with TOP2 and this interaction is critical to ETO sensitivity. Moreover, depletion of ZATT resulted in accelerated TOP2 degradation after ETO or cycloheximide (CHX) treatment, suggesting that ZATT may increase TOP2 stability and likely participate in TOP2 turnover. Taken together, this study suggests that ZATT is a critical determinant that dictates responses to ETO treatment and targeting. ZATT is a promising strategy to increase ETO efficacy for cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway

Park

Zhang

Nie

et al. 2023

IJMS

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“…To survive the stress on TOP2cc, cancer cells have evolved a myriad of DNA repair enzymes and cellular processes to eliminate these covalent TOP2-DNA complexes, resulting in protein-free DSBs, facilitating repair of the unique DSBs by standard DNA repair pathways 7 , 8 . If mis-repaired, DSBs often cause chromosome translocation and genomic instability 9 . A high prevalence of cardiotoxicity and secondary malignancies is linked to TOP2-based medications based on such mechanisms 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

ATM inhibitor KU60019 synergistically sensitizes lung cancer cells to topoisomerase II poisons by multiple mechanisms

Shu

Wang

Yang

et al. 2023

Sci Rep

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Type II topoisomerases (TOP2) poisons represent one class of the most successful and widely prescribed chemotherapeutics, which is frontline therapy for a myriad of systemic cancers and solid tumors, including lymphomas, leukemias, and lung cancer. Despite this, treatment with this class of drugs induces unwanted side effects (including cardiovascular morbidity and secondary malignancies). Additionally, the emergence of drug resistance also greatly compromises the clinical use of these drugs. To enhance therapeutic efficiency while lowering unwanted side effects, new insights into effective combination therapy are required. In this study we found that KU60019, a novel, and highly specific ATM kinase inhibitor interferes with the association of ATM with TOP2β and stabilizes TOP2β-DNA cleavage complex, thereby impairing the repair of TOP2 poison-induced DSBs and contributes to genome stability, leading to accelerated cell death. In H1299 as well as in A549 lung cancer cell lines, biologically, KU60019 combined with VP-16 (one of the TOP2 poisons) synergistically suppressed the growth of cells and survival and triggered a much higher apoptosis rate. In summary, we provide a proof-of-concept strategy that ATM inhibitors combined with TOP2 poison would synergistically suppresses lung cancer cell survival as well as reduce DNA damage responses, thus may lowering the possibility of cardiotoxicity and secondary malignancy linked to therapy.

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“…Etoposide inhibits topoisomerase II activity by stabilising the cleavage complex and prevents DNA replication in cancer cells. 3 However, in this tumour case, despite the use of etoposide, there was no therapeutic effect. Given that the two functionally active domains of TOP2B are conserved, we predict that they up-regulate TOP2B expression.…”

mentioning

confidence: 65%

Aggressive undifferentiated small round cell sarcoma of the thorax showing TOP2B::UBA3 fusion

Nakamura,

Kukita,

Yoshida

et al. 2024

Histopathology

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Regulation of topoisomerase II stability and activity by ubiquitination and SUMOylation: clinical implications for cancer chemotherapy

Cited by 17 publications

References 94 publications

Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway

Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway

ATM inhibitor KU60019 synergistically sensitizes lung cancer cells to topoisomerase II poisons by multiple mechanisms

Aggressive undifferentiated small round cell sarcoma of the thorax showing TOP2B::UBA3 fusion

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