USP39 promotes non-homologous end-joining repair by poly(ADP-ribose)-induced liquid demixing

Kim, Jae Jin; Lee, Seo Yun; Kim, Soyeon; Chung, Jee Min; Park, Sangwook; Yoon, Junghyun; Yun, Hansol; Ji, Jeong‐Seon; Chae, Sunyoung; Cho, Hyeseong; Kim, Chan Gil; Dawson, Ted M.; Kim, Hongtae; Dawson, Valina L.; Kang, Ho Chul

doi:10.1093/nar/gkab892

Cited by 12 publications

(12 citation statements)

References 92 publications

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“…The ubiquitination modification also plays an important role in genome stabilization ( 54 ). Wu et al found that the deubiquitinating enzyme USP37 can act with the helicase BLM to regulate the DNA damage response ( 55 ), and Kim et al also found that ubiquitin enzyme play an important role in poly (ADP-ribose) (PAR) repair of DNA damage ( 56 ). Ubiquitination is also closely related to cancer, among which ubiquitination regulation by tumor inhibitor p53 is one of the classical pathways ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

Jiang

Song

Xiao

et al. 2022

Front. Public Health

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BackgroundDNA damage response and repair (DDR) related signatures play an important role in maintaining genome stability and other biological processes. It also affects the occurrence, development, and treatment of cancer. However, in renal cell carcinoma (RCC), especially clear cell renal carcinoma (ccRCC), the potential association between DDR-related signatures and tumor heterogeneity and tumor microenvironment (TME) remains unclear.MethodsUtilizing unsupervised clustering algorithm, we divided RCC into two subgroups, DCS1 and DCS2, according to the differences in DDR gene expression, and compared the characteristics of the two subgroups through multiple dimensions.ResultsCompared with DCS1, DCS2 patients have higher clinical stage/grade and worse prognosis, which may be related to active metabolic status and immunosuppression status. At the same time, the high mutation rate in DCS2 may also be an important reason for the prognosis. We also analyzed the sensitivity of the two subgroups to different therapeutic agents and established a subtypes' biomarkers-based prognostic system with good validation results to provide ideas for clinical diagnosis and treatment. Finally, we identified a pivotal role for DDX1 in the DDR gene set, which may serve as a future therapeutic target.ConclusionThis study showed that DDR has an important impact on the development and treatment of RCC. DCS2 subtypes have a poor prognosis, and more personalized treatment and follow-up programs may be needed. The assessment of DDR gene mutations in patients may be helpful for clinical decision-making. DDX1 may be one of the effective targets for RCC treatment in the future.

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Section: Discussionmentioning

confidence: 99%

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

Jiang

Song

Xiao

et al. 2022

Front. Public Health

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“…267 Recruitment of XRCC4, LIG4, APTX, and PAXX, all of which are required for NHEJ, follows USP39-PAR PS. 267 Excessive recruitment of USP39 may eventually downregulate HR by depleting BRCA mRNA through its role in the spliceosome. 267,268 Moreover, PAR binding and PS have been observed in a decoupled manner for other proteins.…”

Section: The Dna Damage Response Requires Phase Separation Of Par Rea...mentioning

confidence: 99%

“…267 Excessive recruitment of USP39 may eventually downregulate HR by depleting BRCA mRNA through its role in the spliceosome. 267,268 Moreover, PAR binding and PS have been observed in a decoupled manner for other proteins. For example, p53 is known to oligomerize on PAR chains, 212 p53 can be PARylated, 269 and PS of p53 was recently described in vitro and in vivo.…”

Section: The Dna Damage Response Requires Phase Separation Of Par Rea...mentioning

confidence: 99%

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Regulation of Biomolecular Condensates by Poly(ADP-ribose)

et al. 2023

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Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can nucleate the formation of these condensates by accelerating the self-association of proteins. Poly(ADP-ribose) (PAR) chains are remarkably transient modifications with turnover rates on the order of minutes, yet they can be required for the formation of granules in response to oxidative stress, DNA damage, and other stimuli. Moreover, accumulation of PAR is linked with adverse phase transitions in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In this review, we provide a primer on how PAR is synthesized and regulated, the diverse structures and chemistries of ADP-ribosylation modifications, and protein−PAR interactions. We review substantial progress in recent efforts to determine the molecular mechanism of PAR-mediated phase separation, and we further delineate how inhibitors of PAR polymerases may be effective treatments for neurodegenerative pathologies. Finally, we highlight the need for rigorous biochemical interrogation of ADP-ribosylation in vivo and in vitro to clarify the exact pathway from PARylation to condensate formation.

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“…It was shown before that PAR chains can synergize with various intrinsically disordered proteins, e.g. FUS, to initiate LLPS, however, a recent study described a DUB enzyme to bind PAR chains in a damage-dependent manner ( Kim et al, 2021 ). The USP39 deubiquitinase is recruited to the DSBs by the poly(ADP-ribosyl)ation with help of its tripartite RG domain, thus inducing liquid demixing and promoting NHEJ.…”

Section: Local and Global Chromatin Changes Mediated By Ubiquitinationmentioning

confidence: 99%

Chromatin Ubiquitination Guides DNA Double Strand Break Signaling and Repair

Kolobynina

Rapp

Cardoso

2022

Front. Cell Dev. Biol.

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Chromatin is the context for all DNA-based molecular processes taking place in the cell nucleus. The initial chromatin structure at the site of the DNA damage determines both, lesion generation and subsequent activation of the DNA damage response (DDR) pathway. In turn, proceeding DDR changes the chromatin at the damaged site and across large fractions of the genome. Ubiquitination, besides phosphorylation and methylation, was characterized as an important chromatin post-translational modification (PTM) occurring at the DNA damage site and persisting during the duration of the DDR. Ubiquitination appears to function as a highly versatile “signal-response” network involving several types of players performing various functions. Here we discuss how ubiquitin modifiers fine-tune the DNA damage recognition and response and how the interaction with other chromatin modifications ensures cell survival.

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USP39 promotes non-homologous end-joining repair by poly(ADP-ribose)-induced liquid demixing

Cited by 12 publications

References 92 publications

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

Regulation of Biomolecular Condensates by Poly(ADP-ribose)

Chromatin Ubiquitination Guides DNA Double Strand Break Signaling and Repair

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