The Deubiquitylating Enzyme USP4 Cooperates with CtIP in DNA Double-Strand Break End Resection

Liu, Hailong; Zhang, Haoxing; Wang, Xiaohui; Tian, Qingsong; Hu, Zhaohua; Peng, Changmin; Pei, Jun‐Peng; Wang, Tingting; Wei, Guo; Chen, Yali; Li, Xinzhi; Zhang, Pumin; Pei, Huadong

doi:10.1016/j.celrep.2015.08.056

Cited by 56 publications

(66 citation statements)

References 75 publications

(84 reference statements)

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“…However, the intrinsic pro‐survival signalling could abolish the killing efficiency and lead to cisplatin tolerance and tumour development of melanoma 23, 24. Since that USP4 played a critical role in DNA damage response,16, 17 we proposed that the intervention of USP4 may affect cisplatin‐induced cell apoptosis in melanoma. To this end, we performed flow cytometry analysis to determine the cell apoptotic rate of cisplatin‐treated melanoma cells.…”

Section: Resultsmentioning

confidence: 99%

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Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

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Melanoma is the most malignant skin cancer with increasing incidence worldwide. Although innovative therapies such as BRAF inhibitor and immune checkpoint inhibitor have gained remarkable advances, metastatic melanoma remains an incurable disease for its notorious aggressiveness. Therefore, further clarification of the underlying mechanism of melanoma pathogenesis is critical for the improvement of melanoma therapy. Ubiquitination is an important regulatory event for cancer hallmarks and melanoma development, and the deubiquitinating enzymes including ubiquitin‐specific peptidase (USP) families are greatly implicated in modulating cancer biology. Herein, we first found that the expression of the deubiquitinase USP4 was significantly up‐regulated in melanoma tissues and cell lines. Furthermore, although USP4 knockdown had little impact on melanoma cell proliferation, it could increase the sensitivity to DNA damage agent cisplatin. We subsequently showed that USP4 regulated cisplatin‐induced cell apoptosis via p53 signalling. More importantly, USP4 could accentuate the invasive and migratory capacity of melanoma cells by promoting epithelial‐mesenchymal transition. Altogether, our results demonstrate that the up‐regulated USP4 plays an oncogenic role in melanoma by simultaneously suppressing stress‐induced cell apoptosis and facilitating tumour metastasis.

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Section: Resultsmentioning

confidence: 99%

“…Among them, USP4 is a rather important USP member with previously reported links to cancer associated‐DNA repair and p53 stability 15, 16, 17, 18. On the one hand, the elevated USP4 expression contributed to the growth of colorectal cancer via deubiquitination and stabilization of oncogene PRL‐3 19.…”

Section: Introductionmentioning

confidence: 99%

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

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“…1A). Among them, USP1, USP4, USP11, and UCHL5 have been associated with HR (Wiltshire et al 2010;Murai et al 2011;Nishi et al 2014;Liu et al 2015;Orthwein et al 2015;Wijnhoven et al 2015). However, one of the hits, UCHL3, has not been implicated in DNA repair.…”

Section: Uchl3 Regulates Rad51 Ir-induced Focus Formation (Irif) and Hrmentioning

confidence: 99%

A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination

Luo

et al. 2016

Genes Dev.

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Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2-RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. Overexpression of UCHL3 renders breast cancer cells resistant to radiation and chemotherapy, while depletion of UCHL3 sensitizes cells to these treatments, suggesting a determinant role of UCHL3 in cancer therapy. Overall, we identify UCHL3 as a novel regulator of DNA repair and reveal a model in which a phosphorylation-deubiquitination cascade dynamically regulates the BRCA2-RAD51 pathway.

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“…Yet it may be possible that RNF138 targets additional proteins involved in DSB repair pathway choice (Bekker-Jensen and Mailand, 2015). Interestingly, two independent studies have reported that the deubiquitinase (DUB) activity of USP4 functions in DNA-end resection (Liu et al, 2015; Wijnhoven et al, 2015). They both demonstrated that USP4 interacts with CtIP and MRN and regulates the recruitment of CtIP to DSBs.…”

Section: Ubiquitylation and Sumoylation Of The Dna-end Resection Machmentioning

confidence: 99%

Controlling DNA-End Resection: An Emerging Task for Ubiquitin and SUMO

Himmels

Sartori

2016

Front. Genet.

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DNA double-strand breaks (DSBs) are one of the most detrimental lesions, as their incorrect or incomplete repair can lead to genomic instability, a hallmark of cancer. Cells have evolved two major competing DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR is initiated by DNA-end resection, an evolutionarily conserved process that generates stretches of single-stranded DNA tails that are no longer substrates for religation by the NHEJ machinery. Ubiquitylation and sumoylation, the covalent attachment of ubiquitin and SUMO moieties to target proteins, play multifaceted roles in DNA damage signaling and have been shown to regulate HR and NHEJ, thus ensuring appropriate DSB repair. Here, we give a comprehensive overview about the current knowledge of how ubiquitylation and sumoylation control DSB repair by modulating the DNA-end resection machinery.

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The Deubiquitylating Enzyme USP4 Cooperates with CtIP in DNA Double-Strand Break End Resection

Cited by 56 publications

References 75 publications

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination

Controlling DNA-End Resection: An Emerging Task for Ubiquitin and SUMO

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