Parkin regulates translesion DNA synthesis in response to UV radiation

Zhu, Xuefei; Ma, Xinwen; Tu, Yingfeng; Huang, Min; Li, Hongmei; Wang, Fengli; Gong, Juanjuan; Wang, Jiuqiang; Li, Xiaoling; Chen, Qian; Shen, Haoming; Zhu, Shu; Wang, Yun; Liu, Yang; Guo, Caixia; Tang, Tie-Shan

doi:10.18632/oncotarget.16855

Cited by 10 publications

(24 citation statements)

References 71 publications

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“…Moreover, parkin is translocated to the nucleus in response to DNA damage. In the nucleus, parkin binds to Nijmegen breakage syndrome 1 (NBS1), a protein engaged in DNA double strand break signaling and repair, and ensures its efficient recruitment to UV-induced DNA lesions (Zhu et al, 2017). Parkin also monoubiquitinates proliferating cell nuclear antigen (PCNA), which is an essential co-factor for DNA polymerase δ that is engaged in repair-linked and general DNA replication (Zhu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…In the nucleus, parkin binds to Nijmegen breakage syndrome 1 (NBS1), a protein engaged in DNA double strand break signaling and repair, and ensures its efficient recruitment to UV-induced DNA lesions (Zhu et al, 2017). Parkin also monoubiquitinates proliferating cell nuclear antigen (PCNA), which is an essential co-factor for DNA polymerase δ that is engaged in repair-linked and general DNA replication (Zhu et al, 2017). Taken together, the resulting effects of parkin on DNA repair may underlie the observed increased risk of skin tumors in PD (Zhu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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The interplay between parkin and alpha-synuclein; possible implications for the pathogenesis of Parkinson’s disease

Jęśko¹,

Lenkiewicz²,

Wilkaniec³

et al. 2019

Acta Neurobiologiae Experimentalis

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Parkin and alpha-synuclein (α-syn) are two key proteins involved in the pathophysiology of Parkinson's disease (PD). Oligomerization/ aggregation and excessive secretion of α-syn contributes to PD through free radical stress, mitochondrial impairment, and synaptic dysfunction. Parkin, an E3 ubiquitin ligase, is considered to be a pleiotropic, neuroprotective protein that modulates metabolic turnover and the accumulation of α-syn. This is in addition to parkin's role in counteracting the more distant effects of α-syn on cellular survival by altering proteasomal, autophagic, and calpain-mediated protein degradation pathways that can reduce α-syn levels. Moreover, parkin regulates mitochondrial turnover, cell survival, and immune phenomena-processes that are all known to be disturbed in PD. In addition, parkin might have an impact on the spreading and propagation of α-syn by controlling its post-translational modifications. On the other hand, recent research has shown that α-syn oligomers affect the expression, post-translational modification, and activity of parkin. This review focuses on the molecular mechanisms of cross-talk between parkin and α-syn in PD. The physical and functional interactions between α-syn and parkin, which have been incompletely characterized to-date, may present a new therapeutic avenue in PD and related synucleinopathies. The development of effective, clinically feasible modulators may offer great hopes for the therapy of PD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The interplay between parkin and alpha-synuclein; possible implications for the pathogenesis of Parkinson’s disease

Jęśko¹,

Lenkiewicz²,

Wilkaniec³

et al. 2019

Acta Neurobiologiae Experimentalis

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“…Micronucleus assay was performed as described ( 20 , 30 ). Briefly, U2OS cells transfected with siNC or siSART3 were irradiated with UVC (3 J/m 2 ) followed by incubating with 6 μg/ml Cytochalasin B in complete medium for 48 h. The cells were trypsinized and washed with PBS once, further treated with 0.075 M KCl for 20 min.…”

Section: Methodsmentioning

confidence: 99%

“…Compelling evidence reveals that PCNA-mUb, the key event in TLS, is tightly regulated by several DDR factors, including USP1, MSH2, BRCA1, Polη, REV1 and Parkin ( 15–20 ). In contrast to USP1, which can deubiquitinate PCNA-mUb ( 15 , 21 ), MSH2, BRCA1 and Parkin have been shown to facilitate UV-induced PCNA-mUb through promoting ssDNA generation and RPA focus formation ( 16 , 19 , 20 ). And Polη and REV1, two TLS polymerases, can promote RAD18 recruitment after UV irradiation ( 17 , 18 ).…”

Section: Introductionmentioning

confidence: 99%

RNA-splicing factor SART3 regulates translesion DNA synthesis

Huang

Zhou

Gong

et al. 2018

Nucleic Acids Research

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Translesion DNA synthesis (TLS) is one mode of DNA damage tolerance that uses specialized DNA polymerases to replicate damaged DNA. DNA polymerase η (Polη) is well known to facilitate TLS across ultraviolet (UV) irradiation and mutations in POLH are implicated in skin carcinogenesis. However, the basis for recruitment of Polη to stalled replication forks is not completely understood. In this study, we used an affinity purification approach to isolate a Polη-containing complex and have identified SART3, a pre-mRNA splicing factor, as a critical regulator to modulate the recruitment of Polη and its partner RAD18 after UV exposure. We show that SART3 interacts with Polη and RAD18 via its C-terminus. Moreover, SART3 can form homodimers to promote the Polη/RAD18 interaction and PCNA monoubiquitination, a key event in TLS. Depletion of SART3 also impairs UV-induced single-stranded DNA (ssDNA) generation and RPA focus formation, resulting in an impaired Polη recruitment and a higher mutation frequency and hypersensitivity after UV treatment. Notably, we found that several SART3 missense mutations in cancer samples lessen its stimulatory effect on PCNA monoubiquitination. Collectively, our findings establish SART3 as a novel Polη/RAD18 association regulator that protects cells from UV-induced DNA damage, which functions in a RNA binding-independent fashion.

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“…( A ) Phylogeny of ubiquitin (Ub), ubiquitin-like proteins (UBLs) and Ub/UBL domains fused to human proteins. Genome stability associations are highlighted in green and apply to the following in addition to ISG15: Ub [ 3 , 10 ], Parkin [ 47 , 48 , 49 , 50 ], NEDD8 [ 11 ], UBTD1 [ 51 ], FAT10 [ 12 ], SF3A1 [ 52 ], RAD23A and RAD23B [ 53 ], TMUB1 (aka HOPS) [ 54 , 55 , 56 ], UBL5 (aka HUB1) [ 12 ], UHRF1 [ 57 , 58 , 59 ], ELOB (aka TCEB2) [ 60 ], USP48 [ 61 , 62 ], ATG12 [ 63 ], BAG6 [ 64 ], RBCK1 [ 65 ], BAG1 [ 66 , 67 ], HERPUD1 [ 68 ], UFM1 [ 12 ], UBQLN4 [ 69 ], SUMO1, SUMO2 and SUMO3 [ 70 ]; sequence similarity to ubiquitin is highlighted in the outermost ring ranging from GABARAP (9.59%) in red over a white midpoint to NEDD8 (58%) in blue. Ub/UBL domains are limited to curated UniProt entries.…”

Section: Isg15 and Isgylationmentioning

confidence: 99%

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

2020

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Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.

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Parkin regulates translesion DNA synthesis in response to UV radiation

Cited by 10 publications

References 71 publications

The interplay between parkin and alpha-synuclein; possible implications for the pathogenesis of Parkinson’s disease

The interplay between parkin and alpha-synuclein; possible implications for the pathogenesis of Parkinson’s disease

RNA-splicing factor SART3 regulates translesion DNA synthesis

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

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