RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

Guturi, Kiran Kumar Naidu; Bohgaki, Miyuki; Bohgaki, Toshiyuki; Srikumar, Tharan; Ng, Deborah; Kumareswaran, Ramanan; Ghamrasni, Samah El; Jeon, Justin Y; Patel, Parasvi S.; Eldin, Mohamed Saad; Bristow, Robert G.; Cheung, Pierina; Stewart, Grant S.; Raught, Brian; Hakem, Anne; Hakem, Razqallah

doi:10.1038/ncomms12638

Cited by 36 publications

(24 citation statements)

References 60 publications

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“…Introduction or removal of ubiquitin is also a mechanism of drug resistance, as it modulates the Top2a activities and protein levels through proteasome degradation [53][54][55] . Deficiency in the RNF168 E3 ubiquitin ligase in breast cancer cells, or elevated levels of ubiquitin ligase Mdm2 in osteosarcoma cells, confers resistance to the Top2 poison etoposide, by regulating Top2 activities [53,56] . Ubiquitin-mediated degradation of Top2 also contributes to the level of drug resistance in solid tumors since proteasome inhibition leads to etoposide resistance [57] .…”

Section: Ubiquitinations and Sumoylationsmentioning

confidence: 99%

The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance

Lotz¹,

Lamour²

2020

CDR

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The type 2 DNA topoisomerases (Top2) are conserved enzymes and biomarkers for cell proliferation. The catalytic activities of the human isoform Top2a are essential for the regulation of DNA topology during DNA replication, transcription, and chromosome segregation. Top2a is a prominent target for anti-cancer drugs and is highly regulated by post-translational modifications (PTM). Despite an increasing number of proteomic studies, the extent of PTM in cancer cells and its importance in drug response remains largely uncharacterized. In this review, we highlight the different modifications affecting the human Top2a in healthy and cancer cells, taking advantage of the structure-function information accumulated in the past decades. We also overview the regulation of Top2a by PTM, the level of PTM in cancer cells, and the resistance to therapeutic compounds targeting the Top2 enzyme. Altogether, this review underlines the importance of future studies addressing more systematically the interplay between PTM and Top2 drug resistance.

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Section: Ubiquitinations and Sumoylationsmentioning

confidence: 99%

The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance

Lotz¹,

Lamour²

2020

CDR

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“…UBE1, Ubc13, and Ub recombinant proteins were gifts from C. Arrowsmith (Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada). Recombinant N1ICD (2 μg; Addgene, 47612), recombinant RNF8 (1 μg), UBE1 (0.1 μg; E1), Ubc13 (0.2 μg; E2), Ub (5 μg), and ATP (5 mM) were mixed, and the reactions were incubated at 30°C for 2 hours in buffer containing 50 mM Tris/HCl (pH 7.5), 5 mM MgCl 2 , and 1 mM DTT and examined by immunoblot as previously reported (39).…”

Section: Methodsmentioning

confidence: 99%

Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

Li¹,

Guturi²,

Gautreau³

et al. 2018

Journal of Clinical Investigation

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The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prognosis for breast cancer patients. Our data revealed that in addition to its role in the repair of DSBs, RNF8 regulated Notch1 signaling and cell-fate determination of mammary luminal progenitors. Mechanistically, RNF8 acted as a negative regulator of Notch signaling by ubiquitylating the active NOTCH1 protein (N1ICD), leading to its degradation. Consistent with abnormal activation of Notch signaling and impaired repair of DSBs in Rnf8-mutant mammary epithelial cells, we observed increased risk of mammary tumorigenesis in mouse models for RNF8 deficiency. Notably, deficiency of RNF8 sensitized breast cancer cells to combination of pharmacological inhibitors of Notch signaling and poly(ADP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.

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“…Several lines of evidence have unraveled the diverse roles of USP10 in tumorigenesis as well as malignancy in different cancer types (Guturi et al, 2016;Lin et al, 2013;Sun et al, 2018;Weisberg et al, 2017;Yang et al, 2014;Yuan et al, 2010). Lin et al found that USP10 antagonizes the transcriptional activity of c-Myc by deubiquitinating and stabilizing SIRT6, to inhibit cell growth and tumor formation in colon cancers (Lin et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein

et al. 2019

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Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life-threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor-b (TGF-b) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF-b pathway remains elusive. In this study, using a functional screen of USPs siRNA library, we identified ubiquitin-specific proteases USP10 as a deubiquitinating enzyme (DUB) that sustains the protein level of Smad4 and activates TGF-b signaling. Further analysis showed that USP10 directly interacts with Smad4 and stabilizes it through the cleavage of its proteolytic ubiquitination, thus promoting HCC metastasis. The suppression of USP10 by either shRNAs or catalytic inhibitor Spautin-1 significantly inhibited the migration of HCC cells, whereas the reconstitution of Smad4 was able to efficiently rescue this defect. Overall, our study not only uncovers the regulatory effect of USP10 on the protein abundance of Smad4, but also indicates that USP10 could be regarded as a potential intervention target for the metastatic HCC in Smad4-positive patients.

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RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

Cited by 36 publications

References 60 publications

The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance

The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance

Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein

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