Modification of PCNA by ISG15 Plays a Crucial Role in Termination of Error-Prone Translesion DNA Synthesis

Park, Sungha; Yang, Seung Wook; Yu, Kyung Ryun; Ka, Seung Hyun; Lee, Seong Won; Seol, Jae Hong; Jeon, Young Joo; Chung, Chin Ha

doi:10.1016/j.molcel.2014.03.031

Cited by 113 publications

(129 citation statements)

References 38 publications

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“…We first confirmed that the two mutants lost the E3 ligase activity. Multiple cellular proteins have been reported as the substrates of TRIM25, such as RIG-I, 14-3-3␦, AMF, ATBF1, and PCNA (28,30,(35)(36)(37). We reasoned that TRIM25 overexpression would increase the ubiquitination levels of these proteins as well as that of some unidentified cellular proteins.…”

Section: Resultsmentioning

confidence: 98%

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

Zheng

Wang

et al. 2017

J Virol

131

168

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Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses by binding to viral mRNAs and repressing the translation and/or promoting the degradation of target mRNA. In addition, ZAP regulates the expression of certain cellular genes. Here, we report that tripartite motif-containing protein 25 (TRIM25), a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 abolished ZAP's antiviral activity. The E3 ligase activity of TRIM25 is required for this regulation. TRIM25 mediated ZAP ubiquitination, but the ubiquitination of ZAP itself did not seem to be required for its antiviral activity. Downregulation of endogenous ubiquitin or overexpression of the deubiquitinase OTUB1 impaired ZAP's activity. We provide evidence indicating that TRIM25 modulates the target RNA binding activity of ZAP. These results uncover a mechanism by which the antiviral activity of ZAP is regulated.IMPORTANCE ZAP is a host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1, Sindbis virus, and Ebola virus. ZAP binds directly to target mRNA, and it represses the translation and promotes the degradation of target mRNA. While the mechanisms by which ZAP posttranscriptionally inhibits target RNA expression have been extensively studied, how its antiviral activity is regulated is not very clear. Here, we report that TRIM25, a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 remarkably abolished ZAP's activity. TRIM25 is required for ZAP optimal binding to target mRNA. These results help us to better understand how the antiviral activity of ZAP is regulated.

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Section: Resultsmentioning

confidence: 98%

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

Zheng

Wang

et al. 2017

J Virol

131

168

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“…While it is accepted that the consequences of the inactivation of a single Y-pol must be different from those arising from the global block of all Y-pols, with the exception of p21 [45], the analysis of most inhibitors has been restricted to Polη [36, 51, 53–57, 60, 61]. Moreover, the overexpression/stabilization of TLS inhibitors should be exploited to support their negative role in TLS.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight

2015

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Over the past half-century, we have become increasingly aware of the ubiquity of DNA damage. Under the constant exposure to exogenous and endogenous genomic stress, cells must attempt to replicate damaged DNA. The encounter of replication forks with DNA lesions triggers several cellular responses, including the activation of translesion DNA synthesis (TLS), which largely depends upon specialized DNA polymerases with flexible active sites capable of accommodating bulky DNA lesions. A detrimental aspect of TLS is its intrinsic mutagenic nature, and thus the activity of the TLS polymerases must ideally be restricted to synthesis on damaged DNA templates. Despite their potential clinical importance in chemotherapy, TLS inhibitors have been difficult to identify since a direct assay designed to quantify genomic TLS events is still unavailable. Herein we discuss the methods that have been used to validate TLS inhibitors such as USP1, p21 and Spartan, highlighting research that has revealed their contribution to the control of DNA synthesis on damaged and undamaged templates.

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“…Certain accessory proteins are also critical for TLS. 32−36 However, many questions, including how these TLS pols are selected and recruited for a particular lesion and how the switch among different pols is coordinated, remain unanswered at present. In mammalian cells, TLS is conducted by pol η, pol κ, pol ι, and Rev1 of the Y-family pols and pol ζ of the B-family enzymes.…”

mentioning

confidence: 99%

Mutational Analysis of the C8-Guanine Adduct of the Environmental Carcinogen 3-Nitrobenzanthrone in Human Cells: Critical Roles of DNA Polymerases η and κ and Rev1 in Error-Prone Translesion Synthesis

et al. 2014

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3-Nitrobenzanthrone (3-NBA), a potent mutagen and suspected human carcinogen, is a common environmental pollutant. The genotoxicity of 3-NBA has been associated with its ability to form DNA adducts, including N-(2′-deoxyguanosin-8-yl)-3-aminobenzanthrone (C8-dG-ABA). To investigate the molecular mechanism of C8-dG-ABA mutagenesis in human cells, we have replicated a plasmid containing a single C8-dG-ABA in human embryonic kidney 293T (HEK293T) cells, which yielded 14% mutant progeny. The major types of mutations induced by C8-dG-ABA were G → T > G → A > G → C. siRNA knockdown of the translesion synthesis (TLS) DNA polymerases (pols) in HEK293T cells indicated that pol η, pol κ, pol ι, pol ζ, and Rev1 each have a role in replication across this adduct. The extent of TLS was reduced with each pol knockdown, but the largest decrease (of ∼55% reduction) in the level of TLS occurred in cells with knockdown of pol ζ. Pol η and pol κ were considered the major contributors of the mutagenic TLS, because the mutation frequency (MF) decreased by 70%, when these pols were simultaneously knocked down. Rev1 also is important for mutagenesis, as reflected by the 60% reduction in MF upon Rev1 knockdown, but it probably plays a noncatalytic role by physically interacting with the other two Y-family pols. In contrast, pol ζ appeared to be involved in the error-free bypass of the lesion, because MF increased by 60% in pol ζ knockdown cells. These results provide important mechanistic insight into the bypass of the C8-dG-ABA adduct.

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Modification of PCNA by ISG15 Plays a Crucial Role in Termination of Error-Prone Translesion DNA Synthesis

Cited by 113 publications

References 38 publications

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight

Mutational Analysis of the C8-Guanine Adduct of the Environmental Carcinogen 3-Nitrobenzanthrone in Human Cells: Critical Roles of DNA Polymerases η and κ and Rev1 in Error-Prone Translesion Synthesis

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