Role of NEDD8 and neddylation dynamics in DNA damage response

Luo, Yifan; Su, Yang; Rao, Feng

doi:10.1007/s42764-021-00044-z

Cited by 3 publications

(1 citation statement)

References 109 publications

(125 reference statements)

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“…Recent studies have linked Neddylation more directly to DNA double-strand break repair, and Nedd8 has been demonstrated to be able to locate damaged DNAs [25]. Hence, in order to investigate whether DNA damage occurs after neddylation inhibition in early embryonic development, we detected γH2AX by immuno uorescence, but no difference was found between MLN4924-treated embryos and the control group (Fig S2a).…”

Section: Nuclear Change and Transcription Alteration In Mln4924treate...mentioning

confidence: 92%

Inhibition of neddylation causes early developmental arrestment in mouse embryo because of the zygotic genome activation failure

Yang

Chen

et al. 2023

Preprint

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Background Maternal protein degradation in mammalian preimplantation embryos has yet to be fully understood. One major pathway is the ubiquitin-proteasome system. Recently, new forms of ubiquitination such as neddylation have been found to play important roles in a wide variety of biological processes, including reproduction. However, the molecular mechanism of neddylation in the early embryonic development of mammals is mostly unknown. Methods The zygotes were collected through in vitro fertilization and the expression of marker genes during embryonic development and zygotic genome activation (ZGA) was monitored after 24,48,72,96 hours of culture with MLN4924 (specific inhibition of neddylation) using real-time quantitative PCR. Single-cell RNA sequencing and quantitative PCR were applied to monitor and validate the changes in the downstream transcriptome. We utilized immunofluorescence and Western blotting to detect the expression and localization of proteins in mouse embryos. Results Blocking neddylation in mouse zygotes led to a statistically significant decrease in the cleavage rate to the 2-cell stage. Transcriptional profiling showed genes differentially expressed in pathways involving cell fate determination, cell differentiation, and cytoskeletal proteins. The expressions of zygotic ZGA markers were significantly reducejiand, indicating a significant downstream alteration in relevant pathways leading to the 2-cell stage arrest phenotype. A decrease in the level of RNA polymerase II in the nucleus was detected, showing impaired gene transcription in the embryo. We also identified a decrease in methyltransferase expression and concomitant reduction in histone H3K4 trimethylation, which may be the molecular mechanism of early embryonic developmental arrest caused by neddylation inhibition. Reduction of Yap1 was detected, suggesting aberrant downstream reactions of the Hippo signaling pathway. It also addressed the problem of the neddylation inhibition caused early embryonic arrest. Our study shed light upon new forms of ubiquitination regulating mammalian embryonic development and may contribute to further investigation of female infertility pathology. Conclusions Our data suggest that blocking neddylation leads to ZGA failure, possibly due to a decrease in H3K4me3 caused by a decrease in methyltransferase (KMT2D).

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Section: Nuclear Change and Transcription Alteration In Mln4924treate...mentioning

confidence: 92%

Inhibition of neddylation causes early developmental arrestment in mouse embryo because of the zygotic genome activation failure

Yang

Chen

et al. 2023

Preprint

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Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models

Olaizola¹,

Lee²,

Fernández‐Barrena³

et al. 2022

Journal of Hepatology

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DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability

Foster,

Wang,

Schmidt

2024

Biochemical Journal

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Maintaining stability of the genome requires dedicated DNA repair and signalling processes that are essential for the faithful duplication and propagation of chromosomes. These DNA damage response (DDR) mechanisms counteract the potentially mutagenic impact of daily genotoxic stresses from both exogenous and endogenous sources. Inherent to these DNA repair pathways is the activity of protein factors that instigate repair processes in response to DNA lesions. The regulation, coordination, and orchestration of these DDR factors is carried out, in a large part, by post-translational modifications, such as phosphorylation, ubiquitylation, and modification with ubiquitin-like proteins (UBLs). The importance of ubiquitylation and UBLylation with SUMO in DNA repair is well established, with the modified targets and downstream signalling consequences relatively well characterised. However, the role of dedicated erasers for ubiquitin and UBLs, known as deubiquitylases (DUBs) and ubiquitin-like proteases (ULPs) respectively, in genome stability is less well established, particularly for emerging UBLs such as ISG15 and UFM1. In this review, we provide an overview of the known regulatory roles and mechanisms of DUBs and ULPs involved in genome stability pathways. Expanding our understanding of the molecular agents and mechanisms underlying the removal of ubiquitin and UBL modifications will be fundamental for progressing our knowledge of the DDR and likely provide new therapeutic avenues for relevant human diseases, such as cancer.

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Role of NEDD8 and neddylation dynamics in DNA damage response

Cited by 3 publications

References 109 publications

Inhibition of neddylation causes early developmental arrestment in mouse embryo because of the zygotic genome activation failure

Inhibition of neddylation causes early developmental arrestment in mouse embryo because of the zygotic genome activation failure

Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models

DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability

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