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      USP19 deubiquitinates HDAC1/2 to regulate DNA damage repair and control chromosomal stability

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          Abstract

          Excessive accumulation of DNA damage will generate chromosome stress, leading to various chromosome abnormalities such as chromatin bridge and result in genomic instability. Orchestra procession and regulation of DNA damage repair are vital for keeping genome stability. Despite of the key role of HDAC1/2 in double strand break (DSB) repair, the regulation for their mode of action is less well understood. In this study, we found that deubiquitination enzymes USP19 physically interacts with HDAC1/2 and specifically regulate their K63-linked ubiquitination, which might be crucial for regulation of HDAC1/2 activity in DNA damage repair. Notably, we found that USP19 trans-locate into nucleus upon IR irradiation and is indispensable for normally DNA damage response. In addition, we showed that USP19 play critical role in preventing anaphase bridge formation through regulating DNA damage repair process. Furthermore, the expression level of USP19 is commonly lower or deleted in several types of tumor. These results indicated that USP19 is a key factor in modulating DNA damage repair by targeting HDAC1/2 K63-linked ubiquitination, cells with deletion or decreased expression of USP19 might cause genome instability and even contribute to tumorigenesis.

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          Most cited references21

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          The DNA damage response: ten years after.

          The DNA damage response (DDR), through the action of sensors, transducers, and effectors, orchestrates the appropriate repair of DNA damage and resolution of DNA replication problems, coordinating these processes with ongoing cellular physiology. In the past decade, we have witnessed an explosion in understanding of DNA damage sensing, signaling, and the complex interplay between protein phosphorylation and the ubiquitin pathway employed by the DDR network to execute the response to DNA damage. These findings have important implications for aging and cancer.
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            Ubiquitin ligases: cell-cycle control and cancer.

            A driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs), the activities of which are controlled by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors. Two ubiquitin ligases, the SKP1-CUL1-F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), are responsible for the specific ubiquitylation of many of these regulators. Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.
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              Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase.

              Cells respond to DNA double-strand breaks by recruiting factors such as the DNA-damage mediator protein MDC1, the p53-binding protein 1 (53BP1), and the breast cancer susceptibility protein BRCA1 to sites of damaged DNA. Here, we reveal that the ubiquitin ligase RNF8 mediates ubiquitin conjugation and 53BP1 and BRCA1 focal accumulation at sites of DNA lesions. Moreover, we establish that MDC1 recruits RNF8 through phosphodependent interactions between the RNF8 forkhead-associated domain and motifs in MDC1 that are phosphorylated by the DNA-damage activated protein kinase ataxia telangiectasia mutated (ATM). We also show that depletion of the E2 enzyme UBC13 impairs 53BP1 recruitment to sites of damage, which suggests that it cooperates with RNF8. Finally, we reveal that RNF8 promotes the G2/M DNA damage checkpoint and resistance to ionizing radiation. These results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                10 January 2017
                8 August 2016
                : 8
                : 2
                : 2197-2208
                Affiliations
                1 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of BasicMedical Sciences, Beijing 100850, China
                2 Beijing Institute of Biotechnology, Beijing 100071, China
                3 Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
                Author notes
                Correspondence to: Wei-na Zhang, wnzhang@ 123456ncba.ac.cn
                Article
                11116
                10.18632/oncotarget.11116
                5356792
                27517492
                20ef87dd-b01e-4b56-9e22-62b5ae9ad225
                Copyright: © 2017 Wu et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Research Paper

                Oncology & Radiotherapy
                usp19,hdac1/2,dna repair,genome stability
                Oncology & Radiotherapy
                usp19, hdac1/2, dna repair, genome stability

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