The DNA Double-Strand Break Repair in Glioma: Molecular Players and Therapeutic Strategies

Maksoud, Semer

doi:10.1007/s12035-022-02915-2

Cited by 20 publications

(20 citation statements)

References 437 publications

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“…Studies have shown that proteins with different subcellular localizations play different roles (Engels et al, 2007). As has been established in glioma cells, nuclear survivin inhibits DNA damage repair, while the cytoplasm promotes it as well as the prognosis of different colorectal cancers depending on the localization (Qi et al, 2009;Maksoud, 2022). Survivin exists not only in the cytoplasm but also in the nucleus.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

A nanobody-based molecular toolkit for ubiquitin–proteasome system explores the main role of survivin subcellular localization

Miao

Liu

Ouyang

et al. 2023

Front. Bioeng. Biotechnol.

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Targeted protein degradation is a powerful tool for determining the function of specific proteins nowadays. Survivin is the smallest member of the inhibitor of the apoptosis protein (IAP) family. It exists in the cytoplasm and nucleus of cells, but the exact function of survivin in different subcellular locations retained unclear updates due to the lack of effective and simple technical means. In this study, we created a novel nanoantibody-based molecular toolkit, namely, the ubiquitin–proteasome system (Nb4A-Fc-T2A-TRIM21), that can target to degrade survivin localized in cytoplasmic and cell nuclear by ubiquitinating, and by which to verify the potential roles of survivin subcellular localization. Also, the results showed that the cytoplasmic survivin mainly plays an anti-apoptotic function by directly or indirectly inhibiting the caspase pathway, and the nuclear survivin mainly promotes cell proliferation and participates in the regulation of the cell cycle. In addition, the Nb4A-Fc-T2A-TRIM21 system can degrade the endogenous survivin protein in a large amount by the ubiquitin–proteasome pathway, and the system can provide theoretical support for ubiquitination degradation targeting other endogenous proteins.

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Section: Conclusion and Discussionmentioning

confidence: 99%

A nanobody-based molecular toolkit for ubiquitin–proteasome system explores the main role of survivin subcellular localization

Miao

Liu

Ouyang

et al. 2023

Front. Bioeng. Biotechnol.

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“…MRE11, RAD50, and NBS1 expressions as clinical biomarkers for cancer prognosis and responses to chemotherapies have been reported. High MRE11 expression has been implicated with poor prognosis and chemoresistance in gastric cancer, colon cancer, breast cancer as well as glioma (Altan et al, 2016;Bian et al, 2019;Maksoud, 2022). As MRE11 and NBS1 deficiencies sensitize human cancer cells to etoposide (Hoa et al, 2016), it is worth investigating combination with etoposide and the MRE11 endonuclease inhibitors (PFM 01 and 03) in cancer cell lines as well as tumor xenograft models with different MRE11 expressions.…”

Section: Discussionmentioning

confidence: 99%

Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells

Sun

Soans

Mishina

et al. 2022

Front. Mol. Biosci.

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During a normal topoisomerase II (TOP2) reaction, the enzyme forms a covalent enzyme DNA intermediate consisting of a 5′ phosphotyrosyl linkage between the enzyme and DNA. While the enzyme typically rejoins the transient breakage after strand passage, a variety of conditions including drugs targeting TOP2 can inhibit DNA resealing, leading to enzyme-mediated DNA damage. A critical aspect of the repair of TOP2-mediated damage is the removal of the TOP2 protein covalently bound to DNA. While proteolysis plays a role in repairing this damage, nucleolytic enzymes must remove the phosphotyrosyl-linked peptide bound to DNA. The MRN complex has been shown to participate in the removal of TOP2 protein from DNA following cellular treatment with TOP2 poisons. In this report we used an optimized ICE (In vivo Complex of Enzyme) assay to measure covalent TOP2/DNA complexes. In agreement with previous independent reports, we find that the absence or inhibition of the MRE11 endonuclease results in elevated levels of both TOP2α and TOP2β covalent complexes. We also examined levels of TOP2 covalent complexes in cells treated with the proteasome inhibitor MG132. Although MRE11 inhibition plus MG132 was not synergistic in etoposide-treated cells, ectopic overexpression of MRE11 resulted in removal of TOP2 even in the presence of MG132. We also found that VCP/p97 inhibition led to elevated TOP2 covalent complexes and prevented the removal of TOP2 covalent complexes by MRE11 overexpression. Our results demonstrate the existence of multiple pathways for proteolytic processing of TOP2 prior to nucleolytic processing, and that MRE11 can process TOP2 covalent complexes even when the proteasome is inhibited. The interactions between VCP/p97 and proteolytic processing of TOP2 covalent complexes merit additional investigation.

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“…Although we noted BAX mRNA expression increased particularly after A5 treatment, it is important to mention that apoptosis induced by Bax protein can decrease autophagy by increasing caspase-mediated cleavage of Beclin 40 . Moreover, DDR activation can lead to the signaling of cell death mediated by apoptosis 41 , 42 . Hence, our results also pointed out to DDR machinery activation on GBM cells treated with A5 or C1, as evidenced by the increase of p21 levels, which suggests activation of p53 signaling followed by repression of CCNB1 expression.…”

Section: Discussionmentioning

confidence: 99%

Aporphine and isoquinoline derivatives block glioblastoma cell stemness and enhance temozolomide cytotoxicity

Rodrigues‐Junior

Raminelli

Hassanie

et al. 2022

Sci Rep

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Glioblastoma (GBM) is the most aggressive and common primary malignant brain tumor with limited available therapeutic approaches. Despite improvements in therapeutic options for GBM patients, efforts to develop new successful strategies remain as major unmet medical needs. Based on the cytotoxic properties of aporphine compounds, we evaluated the biological effect of 12 compounds obtained through total synthesis of ( ±)-apomorphine hydrochloride (APO) against GBM cells. The compounds 2,2,2-trifluoro-1-(1-methylene-3,4-dihydroisoquinolin-2(1H)-yl)ethenone (A5) and ( ±)-1-(10,11-dimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl)ethenone (C1) reduced the viability of GBM cells, with 50% inhibitory concentration ranging from 18 to 48 μM in patient‐derived GBM cultures. Our data show that APO, A5 or C1 modulate the expression of DNA damage and apoptotic markers, impair 3D‐gliomasphere growth and reduce the expression of stemness markers. Potential activity and protein targets of A5, C1 or APO were predicted in silico based on PASS and SEA software. Dopamine receptors (DRD1 and 5), CYP2B6, CYP2C9 and ABCB1, whose transcripts were differentially expressed in the GBM cells, were among the potential A5 or C1 target proteins. Docking analyses (HQSAR and 3D-QSAR) were performed to characterize possible interactions of ABCB1 and CYP2C9 with the compounds. Notably, A5 or C1 treatment, but not temozolomide (TMZ), reduced significantly the levels of extracellular ATP, suggesting ABCB1 negative regulation, which was correlated with stronger cytotoxicity induced by the combination of TMZ with A5 or C1 on GBM cells. Hence, our data reveal a potential therapeutic application of A5 and C1 as cytotoxic agents against GBM cells and predicted molecular networks that can be further exploited to characterize the pharmacological effects of these isoquinoline-containing substances.

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The DNA Double-Strand Break Repair in Glioma: Molecular Players and Therapeutic Strategies

Cited by 20 publications

References 437 publications

A nanobody-based molecular toolkit for ubiquitin–proteasome system explores the main role of survivin subcellular localization

A nanobody-based molecular toolkit for ubiquitin–proteasome system explores the main role of survivin subcellular localization

Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells

Aporphine and isoquinoline derivatives block glioblastoma cell stemness and enhance temozolomide cytotoxicity

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