scholarly journals Downregulation of CDC20 Increases Radiosensitivity through Mcl-1/p-Chk1-Mediated DNA Damage and Apoptosis in Tumor Cells

2020 ◽  
Vol 21 (18) ◽  
pp. 6692
Author(s):  
Yang Gao ◽  
Pengbo Wen ◽  
Bin Chen ◽  
Guanshuo Hu ◽  
Lijun Wu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Direct Interaction ◽  
In Vivo Studies ◽  
Glutathione S Transferase ◽  
Cancer Radiotherapy ◽  
Apoptotic Signaling ◽  
Damage Repair ◽  
Radiation Induced ◽  
Apoptotic Pathways

Radiotherapy is an important modality for the local control of human cancers, but the radioresistance induced by aberrant apoptotic signaling is a hallmark of cancers. Restoring the aberrant apoptotic pathways is an emerging strategy for cancer radiotherapy. In this study, we determined that targeting cell division cycle 20 (CDC20) radiosensitized colorectal cancer (CRC) cells through mitochondrial-dependent apoptotic signaling. CDC20 was overexpressed in CRC cells and upregulated after radiation. Inhibiting CDC20 activities genetically or pharmacologically suppressed the proliferation and increased radiation-induced DNA damage and intrinsic apoptosis in CRC cells. Mechanistically, knockdown of CDC20 suppressed the expression of antiapoptotic protein Mcl-1 but not other Bcl-2 family proteins. The expressions of CDC20 and Mcl-1 respond to radiation simultaneously through direct interaction, as evidenced by immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Subsequently, decreased Mcl-1 expression inhibited the expression level of phosphorylated checkpoint kinase 1 (p-Chk1), thereby resulting in impaired DNA damage repair through downregulating the homologous recombination repair protein Rad51 and finally causing apoptotic signaling. In addition, both CDC20 and Chk1 inhibitors together, through in vivo studies, confirmed the radiosensitizing effect of CDC20 via inhibiting Mcl-1 and p-Chk1 expression. In summary, our results indicate that targeting CDC20 is a promising strategy to improve cancer radiotherapy.

scholarly journals Drosophila p53 directs nonapoptotic programs in postmitotic tissue

2019 ◽  
Vol 30 (11) ◽  
pp. 1339-1351 ◽  
Author(s):  
Paula Kurtz ◽  
Amanda E. Jones ◽  
Bhavana Tiwari ◽  
Nichole Link ◽  
Annika Wylie ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Immunoprecipitation ◽  
In Vivo Studies ◽  
Rna Seq ◽  
Radiation Induced ◽  
Cell Death Gene ◽  
Apoptotic Genes ◽  
Genome Scale ◽  
Target Activation

TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. The need for such in vivo studies is underscored by recent challenges to established paradigms, indicating that unappreciated p53 functions contribute to cancer prevention. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing embryo, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We recently showed that a p53 enhancer (p53RErpr) near the cell death gene reaper forms chromatin contacts and enables p53 target activation across long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in adult heads. Moreover, this failure to exhibit apoptotic responses was not associated with altered chromatin contacts. Instead, we determined that p53 does not occupy the p53RErpr enhancer in this postmitotic tissue as it does in embryos. Through comparative RNA-seq and chromatin immunoprecipitation–seq studies of developing and postmitotic tissues, we further determined that p53 regulates distinct transcriptional programs in adult heads, including DNA repair, metabolism, and proteolysis genes. Strikingly, in the postmitotic context, p53-binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.

scholarly journals RBM5-AS1 promotes radioresistance in medulloblastoma through stabilization of SIRT6 protein

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Chuanying Zhu ◽  
Keke Li ◽  
Mawei Jiang ◽  
Siyu Chen
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Xenograft Model ◽  
Clonogenic Survival ◽  
In Vivo Studies ◽  
Radiation Induced ◽  
Non Coding Rnas ◽  
Potential Strategy ◽  
Induced Apoptosis

AbstractCancer stem cells (CSCs) contribute to radioresistance in medulloblastoma. Thus, identification of key regulators of medulloblastoma stemness is critical for improving radiotherapy for medulloblastoma. In the present study, we profiled CSC-related long non-coding RNAs (lncRNAs) between radioresistant and parental medulloblastoma cells. The roles of the lncRNA RBM5-AS1 in the stemness and radiosensitivity of medulloblastoma cells were investigated. We found that RBM5-AS1, a novel inducer of medulloblastoma stemness, was significantly upregulated in radioresistant medulloblastoma cells compared to parental cells. Knockdown of RBM5-AS1 diminished the viability and clonogenic survival of both radioresistant and parental medulloblastoma cells after radiation. Silencing of RBM5-AS1 significantly enhanced radiation-induced apoptosis and DNA damage. In vivo studies confirmed that depletion of RBM5-AS1 inhibited tumor growth and increased radiosensitivity in a medulloblastoma xenograft model. In contrast, overexpression of RBM5-AS1 reduced radiation-induced apoptosis and DNA damage in medulloblastoma cells. Mechanistically, RBM5-AS1 interacted with and stabilized sirtuin 6 (SIRT6) protein. Silencing of SIRT6 reduced the stemness and reinforced radiation-induced DNA damage in medulloblastoma cells. Overexpression of SIRT6 rescued medulloblastoma cells from RBM5-AS1 depletion-induced radiosensitization and DNA damage. Overall, we identify RBM5-AS1 as an inducer of stemness and radioresistance in medulloblastoma. Targeting RBM5-AS1 may represent a potential strategy to overcome the resistance to radiotherapy in this malignancy.

scholarly journals Photoprotective Effect Of Stilbenes And Its Derivatives against Ultraviolet Radiation-Induced Skin Disorders

2018 ◽  
Vol 11 (3) ◽  
pp. 1199-1208 ◽  
Author(s):  
Tava Shelan Nagapan ◽  
Ahmad Rohi Ghazali ◽  
Dayang Fredalina Basri ◽  
Wenna Nallance Lim
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Ultraviolet Radiation ◽  
Biological Activities ◽  
In Vivo Studies ◽  
Skin Disorders ◽  
Cutaneous Toxicity ◽  
Radiation Induced

Ultraviolet radiation (UVR) from sunlight is an environmental human carcinogen. Skin exposure to UVR would increase the oxidative stress, deoxyribonucleic acid (DNA) damage, melanogenesis and photocarcinogenesis. Therefore, development of photoprotective agent is necessary in order to reduce the cutaneous toxicity. The use natural active compounds like stilbenes and its derivatives have gained attention as photoprotection to skin due to its broad biological activities such as antioxidant, anti-inflammatory, anti melanogenesis and chemoprevention. This review article aims to analyse the existing literature on the photoprotective effect of stilbenes and its derivatives which include the resveratrol, pterostilbene, piceatannol and oxyresveratrol on in vitro and in vivo studies. This article describes the stilbenes and its derivatives protect and prevent UVR induced skin disorders via the reduction of oxidative stress, alleviation of DNA damage, inhibition of melanogenesis and anti photocarcinogenic effect.

Radiocontrast media affect radiation-induced DNA damage repair in vitro and in vivo by affecting Akt signalling

2010 ◽  
Vol 94 (1) ◽  
pp. 110-116 ◽  
Author(s):  
Mahmoud Toulany ◽  
Rainer Kehlbach ◽  
H. Peter Rodemann ◽  
Hossein Mozdarani
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Radiocontrast Media ◽  
Damage Repair ◽  
Radiation Induced

scholarly journals LINC-PINT impedes DNA repair and enhances radiotherapeutic response by targeting DNA-PKcs in nasopharyngeal cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
You-hong Wang ◽  
Zhen Guo ◽  
Liang An ◽  
Yong Zhou ◽  
Heng Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Cancer ◽  
Noncoding Rnas ◽  
Dependent Protein Kinase ◽  
Damage Repair ◽  
Dependent Protein ◽  
Cancer Tissues

AbstractRadioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

scholarly journals PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Nan Huang ◽  
Chang Xu ◽  
Liang Deng ◽  
Xue Li ◽  
Zhixuan Bian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
De Novo ◽  
Dna Damage Repair ◽  
Histone Deacetylase 1 ◽  
Damage Repair ◽  
Damage Response

AbstractPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

scholarly journals Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes Absent

2009 ◽  
Vol 284 (24) ◽  
pp. 16066-16070 ◽  
Author(s):  
Navasona Krishnan ◽  
Dae Gwin Jeong ◽  
Suk-Kyeong Jung ◽  
Seong Eon Ryu ◽  
Andrew Xiao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Protein Tyrosine Phosphatases ◽  
Histone H2a ◽  
Eyes Absent ◽  
Damage Repair ◽  
Damage Response

In mammalian cells, the DNA damage-related histone H2A variant H2A.X is characterized by a C-terminal tyrosyl residue, Tyr-142, which is phosphorylated by an atypical kinase, WSTF. The phosphorylation status of Tyr-142 in H2A.X has been shown to be an important regulator of the DNA damage response by controlling the formation of γH2A.X foci, which are platforms for recruiting molecules involved in DNA damage repair and signaling. In this work, we present evidence to support the identification of the Eyes Absent (EYA) phosphatases, protein-tyrosine phosphatases of the haloacid dehalogenase superfamily, as being responsible for dephosphorylating the C-terminal tyrosyl residue of histone H2A.X. We demonstrate that EYA2 and EYA3 displayed specificity for Tyr-142 of H2A.X in assays in vitro. Suppression of eya3 by RNA interference resulted in elevated basal phosphorylation and inhibited DNA damage-induced dephosphorylation of Tyr-142 of H2A.X in vivo. This study provides the first indication of a physiological substrate for the EYA phosphatases and suggests a novel role for these enzymes in regulation of the DNA damage response.

scholarly journals PDTB-10. INHIBITION OF RADIATION-INDUCED DNA DAMAGE REPAIR MEDIATED CHROMATIN MODIFICATION BY HISTONE H3 DEMETHYLASE INHIBITOR IN PEDIATRIC BRAINSTEM GLIOMA

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi151-vi152
Author(s):  
Quanhong Ma ◽  
Andrea Plunti ◽  
Amanda Saratsis ◽  
Rishi Lulla ◽  
Jason R Fangusaro ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Chromatin Modification ◽  
Histone H3 ◽  
Brainstem Glioma ◽  
Damage Repair ◽  
Radiation Induced
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