Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage

An, Hongli; Lu, Yang; Wang, Chen; Gan, Zhixue; Gu, Heng; Zhang, Tao; Huang, Xin; Liu, Yan; Li, Yufeng; Chang, Shing‐Jyh; Lai, Jianghua; Li, Yabin; Su, Chen; Sun, Fang-Lin

doi:10.1128/mcb.00419-16

Cited by 6 publications

(3 citation statements)

References 35 publications

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“…MAD2L2 helps to coordinate the nucleotide insertion and extension steps of lesion bypass ( 36 ). Interestingly, Rad18 and Rad6 are particularly important E2 and E3 enzymes, which function as Ub conjugating and Ub ligase enzymes, respectively, and have been shown to be involved in the UPP, which mediates the degradation of proteins ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin promotes siMAD2L2‑induced apoptosis in colon cancer cells

Zhao

et al. 2021

Mol Med Rep

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The clinical efficacy of colorectal tumor treatment is restricted due to platinum agent resistance. Translesion DNA synthesis (TLS) has been shown to contribute to this resistance; however, the exact molecular mechanism remains unknown. The present study aimed to investigate the possible function of the core of the TLS polymerase mitotic arrest deficient 2 like 2 (MAD2L2) in drug sensitivity, in order to provide a treatment rationale for platinum-based chemotherapy in colon cancer. In the present study, MAD2L2 was knocked down using MAD2L2-specific small interfering (si)RNA. HCT116 and SW620 cells were treated with oxaliplatin and MG132; oxaliplatin is a platinum compound that induces DNA damage and MG132 is a potent proteasome inhibitor. Cell viability was determined using an MTT assay. Cell apoptosis was examined via flow cytometry and TUNEL assay. The activity of proteasome 26S subunit, non-ATPase 13 (PSMD13) was detected using ELISA, while the expression levels of apoptotic-related proteins were detected via western blotting. The results demonstrated that cells treated with oxaliplatin or MG132 alone had decreased viability, but a synergistic effect was not observed after co-treatment. In addition, the knockdown of MAD2L2 caused by siMAD2L2 or oxaliplatin treatment increased the expression levels of the pro-apoptotic proteins Bax and Bak and decreased the expression levels of the anti-apoptotic protein Bcl-2, compared with the negative control group. Moreover, MG132 alleviated the decrease in MAD2L2 expression, while reducing siMAD2L2-induced cell apoptosis. These results indicate that oxaliplatin promotes siMAD2L2-induced apoptosis in colon cancer cells. This process was associated with the Bcl-2 and ubiquitin-proteasome pathway. Overall, the present study provides a theoretical basis for improving the clinical efficacy of colon cancer by combining chemotherapy and gene therapy.

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Section: Discussionmentioning

confidence: 99%

Oxaliplatin promotes siMAD2L2‑induced apoptosis in colon cancer cells

Zhao

et al. 2021

Mol Med Rep

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“…In many cases, chromatin structure and nucleosomal organization often represent a barrier to the DSB repair machinery (Price and D'Andrea, 2013). This model has been supported by various lines of evidence, with our recent work and others showing that a reduction in condensed heterochromatin promotes DSB repair (Goodarzi et al, 2008;Chiolo et al, 2011;Chen et al, 2015;An et al, 2017). Histone H3 with hyper-methylation at lysine 27 causes another type of repressive chromatin and is often associated with gene silencing via polycomb group protein (PcG) repression (Pirrotta, 1998(Pirrotta, , 1997Kingston, 2009, 2013).…”

Section: Resultsmentioning

confidence: 90%

Histone H3K27 methylation modulates the dynamics of FANCD2 on chromatin to facilitate NHEJ and genome stability

Zhang

Chang

Sun

et al. 2018

Journal of Cell Science

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Dysregulation of the homeostatic balance of histone H3 di- and tri-methyl lysine 27 (H3K27me2/3) levels caused by the mis-sense mutation of histone H3 (H3K27M) is reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in patients with diffuse intrinsic pontine glioma (DIPG), dramatically attenuated the presence of 53BP1 (also known as TP53BP1) foci and the capability of non-homologous end joining (NHEJ) in human dermal fibroblasts. H3.1K27M mutant cells showed increased rates of genomic insertions/deletions and copy number variations, as well as an increase in p53-dependent apoptosis. We further showed that both hypo-H3K27me2/3 and H3.1K27M interacted with FANCD2, a central player in the choice of DNA repair pathway. H3.1K27M triggered the accumulation of FANCD2 on chromatin, suggesting an interaction between H3.1K27M and FANCD2. Interestingly, knockdown of FANCD2 in H3.1K27M cells recovered the number of 53BP1-positive foci, NHEJ efficiency and apoptosis rate. Although these findings in HDF cells may differ from the endogenous regulation of the H3.1K27M mutant in the specific tumor context of DIPG, our results suggest a new model by which H3K27me2/3 facilitates NHEJ and the maintenance of genome stability.This article has an associated First Person interview with the first author of the paper.

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“…OTUB1 inhibits the process via deubiquitination of UBE2N. By collaborating with the heterodimeric E3 ligase RNF20/RNF40, RAD6 catalyzes the monoubiquitination of H2B to participate in the regulation of DNA damage repair [ 137 ].…”

Section: Biological Processes Involving E2smentioning

confidence: 99%

The Molecular Basis of Ubiquitin-Conjugating Enzymes (E2s) as a Potential Target for Cancer Therapy

Song

Shen

et al. 2021

IJMS

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Ubiquitin-conjugating enzymes (E2s) are one of the three enzymes required by the ubiquitin-proteasome pathway to connect activated ubiquitin to target proteins via ubiquitin ligases. E2s determine the connection type of the ubiquitin chains, and different types of ubiquitin chains regulate the stability and activity of substrate proteins. Thus, E2s participate in the regulation of a variety of biological processes. In recent years, the importance of E2s in human health and diseases has been particularly emphasized. Studies have shown that E2s are dysregulated in variety of cancers, thus it might be a potential therapeutic target. However, the molecular basis of E2s as a therapeutic target has not been described systematically. We reviewed this issue from the perspective of the special position and role of E2s in the ubiquitin-proteasome pathway, the structure of E2s and biological processes they are involved in. In addition, the inhibitors and microRNAs targeting E2s are also summarized. This article not only provides a direction for the development of effective drugs but also lays a foundation for further study on this enzyme in the future.

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Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage

Cited by 6 publications

References 35 publications

Oxaliplatin promotes siMAD2L2‑induced apoptosis in colon cancer cells

Oxaliplatin promotes siMAD2L2‑induced apoptosis in colon cancer cells

Histone H3K27 methylation modulates the dynamics of FANCD2 on chromatin to facilitate NHEJ and genome stability

The Molecular Basis of Ubiquitin-Conjugating Enzymes (E2s) as a Potential Target for Cancer Therapy

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