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 ◽  
...  

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.

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Chuanying Zhu ◽  
Keke Li ◽  
Mawei Jiang ◽  
Siyu Chen

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.


2018 ◽  
Vol 11 (3) ◽  
pp. 1199-1208 ◽  
Author(s):  
Tava Shelan Nagapan ◽  
Ahmad Rohi Ghazali ◽  
Dayang Fredalina Basri ◽  
Wenna Nallance Lim

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.


2020 ◽  
Vol 21 (18) ◽  
pp. 6692
Author(s):  
Yang Gao ◽  
Pengbo Wen ◽  
Bin Chen ◽  
Guanshuo Hu ◽  
Lijun Wu ◽  
...  

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.


Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3470
Author(s):  
Aubrey L. Miller ◽  
Patrick L. Garcia ◽  
Samuel C. Fehling ◽  
Tracy L. Gamblin ◽  
Rebecca B. Vance ◽  
...  

Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.


2015 ◽  
Vol 115 ◽  
pp. S581-S582
Author(s):  
M. Ebert ◽  
B. Dahl ◽  
J. Prunster ◽  
N. Zeps ◽  
B. Reniers ◽  
...  

2019 ◽  
Vol 15 (35) ◽  
pp. 4105-4118 ◽  
Author(s):  
Lina Lu ◽  
Wenjun Li ◽  
Lihua Chen ◽  
Qiong Su ◽  
Yanbin Wang ◽  
...  

Aim: To systematically review the prophylactic and therapeutic interventions for reducing the incidence or severity of intestinal symptoms among cancer patients receiving radiotherapy. Materials & methods: A literature search was conducted in the PubMed database using various search terms, including ‘radiation enteritis’, ‘radiation enteropathy’, ‘radiation-induced intestinal disease’, ‘radiation-induced intestinal damage’ and ‘radiation mucositis’. The search was limited to in vivo studies, clinical trials and meta-analyses published in English with no limitation on publication date. Other relevant literature was identified based on the reference lists of selected studies. Results: The pathogenesis of acute and chronic radiation-induced intestinal damage as well as the prevention and treatment approaches were reviewed. Conclusion: There is inadequate evidence to strongly support the use of a particular strategy to reduce radiation-induced intestinal damage. More high-quality randomized controlled trials are required for interventions with limited evidence suggestive of potential benefits.


2010 ◽  
Vol 30 (12) ◽  
pp. 2971-2982 ◽  
Author(s):  
Eladio Abreu ◽  
Elena Aritonovska ◽  
Patrick Reichenbach ◽  
Gaël Cristofari ◽  
Brad Culp ◽  
...  

ABSTRACT Recruitment to telomeres is a pivotal step in the function and regulation of human telomerase; however, the molecular basis for recruitment is not known. Here, we have directly investigated the process of telomerase recruitment via fluorescence in situ hybridization (FISH) and chromatin immunoprecipitation (ChIP). We find that depletion of two components of the shelterin complex that is found at telomeres—TPP1 and the protein that tethers TPP1 to the complex, TIN2—results in a loss of telomerase recruitment. On the other hand, we find that the majority of the observed telomerase association with telomeres does not require POT1, the shelterin protein that links TPP1 to the single-stranded region of the telomere. Deletion of the oligonucleotide/oligosaccharide binding fold (OB-fold) of TPP1 disrupts telomerase recruitment. In addition, while loss of TPP1 results in the appearance of DNA damage factors at telomeres, the DNA damage response per se does not account for the telomerase recruitment defect observed in the absence of TPP1. Our findings indicate that TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells and that recruitment does not depend on POT1 or interaction of the shelterin complex with the single-stranded region of the telomere.


2020 ◽  
Vol 99 (3) ◽  
pp. 253-258
Author(s):  
Е.Э. E. Калюжная ◽  
А.Ю. Yu. Просеков ◽  
Валентин Павлович Волобаев

Introduction. Consistency of fluoride excess in the human environment and professional contact with fluoride is an actual and underestimated problem. Fluoride ion is able to displace the hydroxyl group in calcium hydroxyapatites, forming stable crystals of mixed form of apatites, inducing bone pathology, fluorosis. Despite the high prevalence of fluorosis, there are only a few studies discussing the ability of fluoride ion to increase the level of genotoxic effects. At the same time, such studies are in high demand in connection with a direct correlation between genetic instability and the risk of carcinogenesis. Material and methods. A literature search was conducted according the following queries: “fluoride, fluoride ion, fluorides, DNA damage, genetic damage, genotoxicity.” The search was conducted on the databases PubMed, MEDLINE, Embase and Google Scholar for various articles (all publications until June 2018). All publications were analyzed and included in this review. Results.The present review examines the results of studies aimed at investigation of the ability of fluoride to induce DNA damage, published since the 50-s of 20th century to the present. The analyse of data about genotoxic and mutagenic properties of fluorine observed in In vitro and In vivo studies is provided. It is summarized that at concentrations of sodium fluoride in drinking water of more than 1 mM, fluoride ion has the ability to induce DNA damage and increase the frequency of clastogenic effects in humans and large monkeys. At the same time, for a significant increase in genotoxic effects in rodents, large concentrations of fluorides are required. The main hypotheses about the mechanisms of the fluoride genotoxic properties are described. Conclusion. Considering results published nowadays, it can be noted that fluoride ion obviously showes a number of genotoxic features and can have mutagenic properties in case of chronic and direct contact with cellular objects. It remains questionable issue about genotoxic risk accompanied human contact with fluoride compounds.


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