RNF8 promotes efficient DSB repair by inhibiting the pro‐apoptotic activity of p53 through regulating the function of Tip60

Chen, Hongyu; Shan, Jin; Liu, Jialing; Feng, Yunpeng; Ke, Yueshuang; Qi, Wenjing; Liu, Wenguang; Zeng, Xianlu

doi:10.1111/cpr.12780

Cited by 8 publications

(21 citation statements)

References 57 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). In light of the functional basis of RNF8 is basically to interact with its targets, we thought identifying its direct targets and interacting proteins is more useful to understand how RNF8 participates in various biological processes like LC-MS compared to other highthroughput omics.…”

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

confidence: 79%

“…RNF8 was then recruited to the DNA double-strand breaks site through FHA domain-mediated interaction with MDC1(50, 51) and stabilizes JMJD1C demethylase, demethylating MDC1 at K45, which promotes MDC1 association with RNF8(52). RNF8 then couples with Ubc13, DYRK2, L3MBTL2 to catalyze the formation of K63-linked polyubiquitin chains on many chromatin substrates, including histones H2A, H2AX, and H1 (22,53), which result in the recruitment of DNA repair proteins including 53BP1, BRCA1, and RAD51 to facilitate NHEJ or HR repair. RNF8 also regulates the abundance of the nonhomologous end-joining (NHEJ) repair protein KU80 and JMJ2A via catalyzing K48-linked polyubiquitination at sites of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…This ubiquitin signaling promotes the subsequent recruitment of multiple DNA damage repair factors such as 53BP1, BRCA1, enabling the Homologous Directed Repair. In addition, RNF8 targets non-homologous end joining factor KU (KU70/KU80) for K48-linked ubiquitination(6), and promote e cient DSB damage repair by decreasing the pro-apoptosis activity of p53 through regulating Tip60 protein activity (7).…”

Section: Introductionmentioning

confidence: 99%

“…Except for DNA double-stranded breaks repair, RNF8 was also found to play important roles in various biological processes (7,8), such as chromatin remodeling (9), in ammation signaling (10), spermatogenesis (1,11), telomere maintenance, and end protection (12), via interacting with divergent target proteins. For that, RNF8 can be partly recognized as the "Guardian" of our cells.…”

Section: Introductionmentioning

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%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Functional Reference Map of RNF8 Interactome in Cancers

Liu,

Kuang,

Wang

et al. 2022

Preprint

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“…The resulting constructs were validated by sequencing. The shRNA oligos used have been previously described ( 37 , 38 ). For lentiviral production and infection, HEK293T cells were transfected with a shRNA-expressing plasmid (10 µg), an envelope plasmid (pMD2.G, 2.5 µg) and a packaging plasmid (psPAX2, 7.5 µg) using Lipofectamine 2000 regent according to manufacturer’s instruction.…”

Section: Methodsmentioning

confidence: 99%

The CK1δ/ϵ-Tip60 Axis Enhances Wnt/β-Catenin Signaling via Regulating β-Catenin Acetylation in Colon Cancer

Ning

Sun

et al. 2022

Front. Oncol.

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Casein kinase 1δ/ϵ (CK1δ/ϵ) are well-established positive modulators of the Wnt/β-catenin signaling pathway. However, the molecular mechanisms involved in the regulation of β-catenin transcriptional activity by CK1δ/ϵ remain unclear. In this study, we found that CK1δ/ϵ could enhance β-catenin-mediated transcription through regulating β-catenin acetylation. CK1δ/ϵ interacted with Tip60 and facilitated the recruitment of Tip60 to β-catenin complex, resulting in increasing β-catenin acetylation at K49. Importantly, Tip60 significantly enhanced the SuperTopFlash reporter activity induced by CK1δ/ϵ or/and β-catenin. Furthermore, a CK1δ/CK1ϵ/β-catenin/Tip60 complex was detected in colon cancer cells. Simultaneous knockdown of CK1δ and CK1ϵ significantly attenuated the interaction between β-catenin and Tip60. Notably, inhibition of CK1δ/ϵ or Tip60, with shRNA or small molecular inhibitors downregulated the level of β-catenin acetylation at K49 in colon cancer cells. Finally, combined treatment with CK1 inhibitor SR3029 and Tip60 inhibitor MG149 had more potent inhibitory effect on β-catenin acetylation, the transcription of Wnt target genes and the viability and proliferation in colon cancer cells. Taken together, our results revealed that the transcriptional activity of β-catenin could be modulated by the CK1δ/ϵ-β-catenin-Tip60 axis, which may be a potential therapeutic target for colon cancer.

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FAM135B sustains the reservoir of Tip60‐ATM assembly to promote DNA damage response

Zhang

Liu

et al. 2022

Clinical & Translational Med

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Background Recently, the mechanism by which cells adapt to intrinsic and extrinsic stresses has received considerable attention. Tat‐interactive protein 60‐kDa/ataxia–telangiectasia‐mutated (TIP60/ATM) axis‐mediated DNA damage response (DDR) is vital for maintaining genomic integrity. Methods Protein levels were detected by western blot, protein colocalisation was examined by immunofluorescence (IF) and protein interactions were measured by co‐immunoprecipitation, proximity ligation assay and GST pull‐down assays. Flow cytometry, comet assay and IF assays were used to explore the biological functions of sequence similarity 135 family member B (FAM135B) in DDR. Xenograft tumour, FAM135B transgenic mouse models and immunohistochemistry were utilised to confirm in vitro observations. Results We identified a novel DDR regulator FAM135B which could protect cancer cells from genotoxic stress in vitro and in vivo. The overexpression of FAM135B promoted the removal of γH2AX and 53BP1 foci, whereas the elimination of FAM135B attenuated these effects. Consistently, our findings revealed that FAM135B could promote homologous recombination and non‐homologous end‐joining repairs. Further study demonstrated that FAM135B physically bound to the chromodomain of TIP60 and improved its histone acetyltransferase activity. Moreover, FAM135B enhanced the interactions between TIP60 and ATM under resting conditions. Intriguingly, the protein levels of FAM135B dramatically decreased following DNA damage stress but gradually increased during the DNA repair period. Thus, we proposed a potential DDR mechanism where FAM135B sustains a reservoir of pre‐existing TIP60‐ATM assemblies under resting conditions. Once cancer cells suffer DNA damage, FAM135B is released from TIP60, and the functioning pre‐assembled TIP60‐ATM complex participates in DDR. Conclusions : We characterised FAM135B as a novel DDR regulator and further elucidated the role of the TIP60‐ATM axis in response to DNA damage, which suggests that targeting FAM135B in combination with radiation therapy or chemotherapy could be a potentially effective approach for cancer treatment.

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RNF8 promotes efficient DSB repair by inhibiting the pro‐apoptotic activity of p53 through regulating the function of Tip60

Cited by 8 publications

References 57 publications

A Functional Reference Map of RNF8 Interactome in Cancers

A Functional Reference Map of RNF8 Interactome in Cancers

The CK1δ/ϵ-Tip60 Axis Enhances Wnt/β-Catenin Signaling via Regulating β-Catenin Acetylation in Colon Cancer

FAM135B sustains the reservoir of Tip60‐ATM assembly to promote DNA damage response

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