ArticleOncogene2018
The deubiquitylase USP15 regulates topoisomerase II alpha to maintain genome integrity.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 38 citations in OpenAlex.
- Bibliometrics and potential gene analysis of post-translational modifications in lung cancer.Journal of thoracic disease · 2025Article
- Ubiquitin-specific protease 15 interacts directly with the HSV-1 alkaline nuclease and facilitates viral recombination and replication fork stability.Journal of virology · 2025Article
- Inhibition of UBE2C Promotes Parkin-Mediated K63-Linked Ubiquitination of TOP2A to Induce Senescence and Increase Sensitivity of Doxorubicin in Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Review
- In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer.Nature communications · 2024Article
- Deubiquitylating Enzymes in Cancer and Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Review
- Cancer chemoresistance and its mechanisms: Associated molecular factors and its regulatory role.Medical oncology (Northwood, London, England) · 2023Review
- O-GlcNAcylation promotes topoisomerase IIα catalytic activity in breast cancer chemoresistance.EMBO reports · 2023Article
- Ubiquitin-proteasome system as a target for anticancer treatment-an update.Archives of pharmacal research · 2023Review
- BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification.Molecular cancer research : MCR · 2023Article
- Article
- GINS1 promotes the proliferation and migration of glioma cells through USP15-mediated deubiquitination of TOP2A.iScience · 2022Article
- Human topoisomerases and their roles in genome stability and organization.Nature reviews. Molecular cell biology · 2022Review
- USP15 in Cancer and Other Diseases: From Diverse Functionsto Therapeutic Targets.Biomedicines · 2022Review
- USP15 and USP4 facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1.Cell death discovery · 2022Article
- The regulation of DNA supercoiling across evolution.Protein science : a publication of the Protein Society · 2021Review
- Regulation of topoisomerase II stability and activity by ubiquitination and SUMOylation: clinical implications for cancer chemotherapy.Molecular biology reports · 2021Review
- Review
- USP15: a review of its implication in immune and inflammatory processes and tumor progression.Genes and immunity · 2021Review
- The Multifaceted Roles of USP15 in Signal Transduction.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Ubiquitin-specific protease 15 (USP15) is a widely expressed deubiquitylase that has been implicated in diverse cellular processes in cancer. Here we identify topoisomerase II (TOP2A) as a novel protein that is regulated by USP15. TOP2A accumulates during G2 and functions to decatenate intertwined sister chromatids at prophase, ensuring the replicated genome can be accurately divided into daughter cells at anaphase. We show that USP15 is required for TOP2A accumulation, and that USP15 depletion leads to the formation of anaphase chromosome bridges. These bridges fail to decatenate, and at mitotic exit form micronuclei that are indicative of genome instability. We also describe the cell cycle-dependent behaviour for two major isoforms of USP15, which differ by a short serine-rich insertion that is retained in isoform-1 but not in isoform-2. Although USP15 is predominantly cytoplasmic in interphase, we show that both isoforms move into the nucleus at prophase, but that isoform-1 is phosphorylated on its unique S229 residue at mitotic entry. The micronuclei phenotype we observe on USP15 depletion can be rescued by either USP15 isoform and requires USP15 catalytic activity. Importantly, however, an S229D phospho-mimetic mutant of USP15 isoform-1 cannot rescue either the micronuclei phenotype, or accumulation of TOP2A. Thus, S229 phosphorylation selectively abrogates this role of USP15 in maintaining genome integrity in an isoform-specific manner. Finally, we show that USP15 isoform-1 is preferentially upregulated in a panel of non-small cell lung cancer cell lines, and propose that isoform imbalance may contribute to genome instability in cancer. Our data provide the first example of isoform-specific deubiquitylase phospho-regulation and reveal a novel role for USP15 in guarding genome integrity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.