RNF8-mediated regulation of Akt promotes lung cancer cell survival and resistance to DNA damage

Xu, Yongjie; Hu, Yumeng; Xu, Tao; Ke, Yan; Zhang, Ting; Li, Qin; Chang, Fen; Guo, Xueyuan; Peng, Jingyu; Li, Mo; Zhao, Min; Zhen, Hongying; Xu, Long; Zheng, Duo; Li, Li; Shao, Genze

doi:10.1016/j.celrep.2021.109854

Cited by 27 publications

(32 citation statements)

References 52 publications

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“…The distinct and critical roles of RNF8 in tumorigenesis, cancer progression and resistance to chemotherapy are found both in our results and many previous reports (2,3,(33)(34)(35). We are thereof quite curious about how RNF8 regulate such abundant and different biological processes such as breast cancer metastasis (3,33), lung cancer tumorigenesis(16), DNA double-stranded breaks repair (7,8), chromatin remodeling (9) and spermatogenesis (1,11).…”

Section: The Identi Cation Of Rnf8 Interactome Via Lc-mssupporting

confidence: 79%

“…Down-modulation of RNF8 also enhances cancer cell radiosensitivity (41). While another face of RNF8 is to promote lung cancer tumorigenesis, chemoresistance (2,35), and promote breast cancer metastasis(3), like a "Villain". In light of the structure of RNF8 and the way RNF8 functions, we utilize LC-MS to identify its direct targets and interacting proteins in order to understand how RNF8 participates in distinct biological processes.…”

Section: Discussionmentioning

confidence: 99%

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A Functional Reference Map of RNF8 Interactome in Cancers

Liu,

Kuang,

Wang

et al. 2022

Preprint

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BackgroundRNF8 was an E3 ligase identiﬁed as a critical DNA damage-responsive protein. Recently, massive reports showed that RNF8 could be used as an important therapeutic target for cancer chemo/radiotherapy. However, the in-depth understanding of RNF8 remains limited for the lack of its interactome reference map and comprehensive analysis in divergent cancers, which underscore the need to identify the interactome of RNF8 via high-throughput methods. ResultsA two-way identification method based on LC-MS was designed for the identification of RNF8 interactome with high-specificity. By in silico analysis and in vitro validation, we identified a new reference map of RNF8 interactome network containing substantial new targets, such as YBX1, DNMT1, and HDCA1, new biological functions and the gene-disease associations of RNF8. Our results implied a close relationship between RNF8 and neurodegenerative diseases or tumor-infiltrating immune cells using bulk RNA-seq and scRNA-seq datasets. As a proof of concept of our interactome map, we validated the direct binding between RNF8 and YBX1, and showed that RNF8 catalyzed the ubiquitination of YBX. These results demonstrated that RNF8 might be a crucial regulator of YBX1.ConclusionsOur work provides a unique framework for researchers and clinicians who seek to better explore or understand RNF8-regulated biological functions in cancers. This study hopefully will facilitate rational design and further development of anti-RNF8 therapy in cancers.

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Section: The Identi Cation Of Rnf8 Interactome Via Lc-mssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

A Functional Reference Map of RNF8 Interactome in Cancers

Liu,

Kuang,

Wang

et al. 2022

Preprint

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“…2a ). RNF8 was recently suggested to act as a critical modulator of Akt kinase activation through direct K63-linked ubiquitylation both under physiological and genotoxic conditions 58 (Fig. 2a ).…”

Section: Non-proteolytic Ubiquitylation In the Dna Damage Response (Ddr)mentioning

confidence: 99%

Non-proteolytic ubiquitylation in cellular signaling and human disease

2022

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Ubiquitylation is one of the most common post-translational modifications (PTMs) of proteins that frequently targets substrates for proteasomal degradation. However it can also result in non-proteolytic events which play important functions in cellular processes such as intracellular signaling, membrane trafficking, DNA repair and cell cycle. Emerging evidence demonstrates that dysfunction of non-proteolytic ubiquitylation is associated with the development of multiple human diseases. In this review, we summarize the current knowledge and the latest concepts on how non-proteolytic ubiquitylation pathways are involved in cellular signaling and in disease-mediating processes. Our review, may advance our understanding of the non-degradative ubiquitylation process.

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“…RNF8 was demonstrated to activate Ubc13 and recruit K63-linked poly-ubiquitin conjugation to histones H2A/H2AX, thus contributing to breast cancer predisposition ( Vuorela et al, 2011 ). Moreover, RNF8 utilizes the RING domain, mediating Lys63-linked Ub chains, which is required for DNA double-strand break (DSB) signaling and the downstream BRCA1 tumor suppressor recruitment or lung cancer cell proliferation ( Hodge et al, 2016 ; Xu et al, 2021 ). Inhibiting the Ubc13/Uev1A complex specifically, which is critical for Lys63-linked ubiquitination, promotes ubiquitin conjugation at the Lys147 site, thereby upregulating NF-кB signaling in multiple myeloma and other cancers ( Gallo et al, 2014 ).…”

Section: The Roles Of Non-proteolytic Ubiquitination In Tumorigenesismentioning

confidence: 99%

“…SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) methylates Akt and functions as a scaffold to recruit JMJD2A, which then binds TRAF6 and Skp2-SCF to the Akt complex, thereby promoting tumor development in lung cancer ( Wang et al, 2019 ). Notably, numbers of E3 ligase have been discovered to catalyze K63-linked ubiquitination chains, which are involved in activating NF-κB or Akt signaling pathway, acting as tumor promoters and facilitating tumor progression ( Ji et al, 2021 ; Xu et al, 2021 ; Yu et al, 2021 ; Zhou et al, 2021 ; Zhu et al, 2021 ; He et al, 2022 ). Lys63 poly-ubiquitin chains were also found to be involved in driving the cell cycle and promoting cancer progression ( Kolapalli et al, 2021 ).…”

Section: The Roles Of Non-proteolytic Ubiquitination In Tumorigenesismentioning

confidence: 99%

Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis

Yin

Liu

et al. 2022

Front. Cell Dev. Biol.

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Ubiquitination is a critical type of protein post-translational modification playing an essential role in many cellular processes. To date, more than eight types of ubiquitination exist, all of which are involved in distinct cellular processes based on their structural differences. Studies have indicated that activation of the ubiquitination pathway is tightly connected with inflammation-related diseases as well as cancer, especially in the non-proteolytic canonical pathway, highlighting the vital roles of ubiquitination in metabolic programming. Studies relating degradable ubiquitination through lys48 or lys11-linked pathways to cellular signaling have been well-characterized. However, emerging evidence shows that non-degradable ubiquitination (linked to lys6, lys27, lys29, lys33, lys63, and Met1) remains to be defined. In this review, we summarize the non-proteolytic ubiquitination involved in tumorigenesis and related signaling pathways, with the aim of providing a reference for future exploration of ubiquitination and the potential targets for cancer therapies.

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RNF8-mediated regulation of Akt promotes lung cancer cell survival and resistance to DNA damage

Cited by 27 publications

References 52 publications

A Functional Reference Map of RNF8 Interactome in Cancers

A Functional Reference Map of RNF8 Interactome in Cancers

Non-proteolytic ubiquitylation in cellular signaling and human disease

Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis

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