scholarly journals Interleukin enhancer‐binding factor 2 promotes cell proliferation and DNA damage response in metastatic melanoma

2021 ◽  
Vol 11 (10) ◽  
Author(s):  
Xiaoqing Zhang ◽  
Matias A. Bustos ◽  
Rebecca Gross ◽  
Romela Irene Ramos ◽  
Teh‐Ling Takeshima ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Metastatic Melanoma ◽  
Dna Damage Response ◽  
Binding Factor ◽  
Damage Response

scholarly journals The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response

2021 ◽  
Vol 22 (18) ◽  
pp. 9900
Author(s):  
Siti A. M. Imran ◽  
Muhammad Dain Yazid ◽  
Wei Cui ◽  
Yogeswaran Lokanathan
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Response Factors ◽  
Telomere Repeat ◽  
Protection Mechanism ◽  
Dna Instability ◽  
Binding Factor ◽  
Damage Response ◽  
Dna Break

Telomere repeat binding factor 2 (TRF2) has a well-known function at the telomeres, which acts to protect the telomere end from being recognized as a DNA break or from unwanted recombination. This protection mechanism prevents DNA instability from mutation and subsequent severe diseases caused by the changes in DNA, such as cancer. Since TRF2 actively inhibits the DNA damage response factors from recognizing the telomere end as a DNA break, many more studies have also shown its interactions outside of the telomeres. However, very little has been discovered on the mechanisms involved in these interactions. This review aims to discuss the known function of TRF2 and its interaction with the DNA damage response (DDR) factors at both telomeric and non-telomeric regions. In this review, we will summarize recent progress and findings on the interactions between TRF2 and DDR factors at telomeres and outside of telomeres.

scholarly journals Computational correction of off-targeting for CRISPR-Cas9 essentiality screens

2019 ◽  
Author(s):  
Alexendar R. Perez ◽  
Laura Sala ◽  
Richard K. Perez ◽  
Joana A. Vidigal
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Large Scale ◽  
Computational Method ◽  
Seamless Integration ◽  
Guide Rnas ◽  
Cycle Arrest ◽  
Damage Response

Off-target cleavage by Cas9 can confound measurements of cell proliferation/viability in CRISPR assays by eliciting a DNA-damage response that includes cell cycle arrest1-3. This gene-independent toxicity has been documented in large scale assays2-4 and shown to be a source of false-positives when libraries are populated by promiscuous guide RNAs (gRNAs)7. To address this, we developed CSC, a computational method to correct for the effect of specificity on gRNA depletion. We applied CSC to screening data from the Cancer Dependency Map and show that it significantly improves the specificity of CRISPR-Cas9 essentiality screens while preserving known gene essentialities even for genes targeted by highly pro-miscuous guides. We packaged CSC in a Python software to allow its seamless integration into current CRISPR analysis pipelines and improve the sensitivity of essentiality screens for repetitive genomic loci.

scholarly journals Pseudolaric acid B inhibits neuroglioma cell proliferation through DNA damage response

2017 ◽  
Vol 38 (4) ◽  
pp. 2211-2218 ◽  
Author(s):  
Fengmei Song ◽  
Xiaoyan Yu ◽  
Haipeng Zhang ◽  
Zengyan Wang ◽  
Yue Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Pseudolaric Acid B ◽  
Damage Response

scholarly journals The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways

Oncogene ◽  
2009 ◽  
Vol 28 (12) ◽  
pp. 1506-1517 ◽  
Author(s):  
L Mattera ◽  
F Escaffit ◽  
M-J Pillaire ◽  
J Selves ◽  
S Tyteca ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Cancer Cell ◽  
Dna Damage Response ◽  
Colorectal Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Damage Response

scholarly journals HSATII RNA is induced via a non-canonical ATM-regulated DNA-damage response pathway and facilitates tumor cell proliferation and movement

2020 ◽  
Author(s):  
Maciej T. Nogalski ◽  
Thomas Shenk
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Rna Expression ◽  
Tumor Cell Proliferation ◽  
Dna Damaging Agents ◽  
Damage Response ◽  
Infected Cells ◽  
Dna Damage Response Pathway

ABSTRACTPericentromeric human satellite II (HSATII) repeats are normally silent, but can be actively transcribed in tumor cells, where increased HSATII copy number is associated with a poor prognosis in colon cancer, and in human cytomegalovirus (HCMV)-infected cells, where the RNA facilitates viral replication. Here, we report that HCMV infection or treatment of ARPE-19 diploid epithelial cells with the DNA-damaging agents, etoposide and zeocin, induced HSATII RNA expression, and a kinase-independent function of ATM was required for the induction. Additionally, various breast cancer cell lines growing in adherent, 2-dimensional cell culture expressed HSATII RNA at different levels, and levels were markedly increased when cells were either infected with HCMV or treated with zeocin. High levels of HSATII RNA expression correlated with enhanced migration of breast cancer cells, and knockdown of HSATII RNA reduced cell migration and the rate of cell proliferation. Our investigation links high expression of HSATII RNA to the DNA damage response, centered on a non-canonical function of ATM, and demonstrates a role for the satellite RNA in tumor cell proliferation and movement.SIGNIFICANCEHSATII RNA is associated with cancer progression, immunostimulation and, as we recently reported, it plays an important role in herpesvirus infections. However, the understanding of cellular processes responsible for the expression of HSATII RNA has been limited. Our current investigation identified a non-canonical, ATM kinase-independent DNA-damage response pathway as a common cellular mechanism regulating HSATII RNA induction in virus-infected cells or cells treated with DNA-damaging agents. Additionally, our study provides a link between expression of HSATII RNA and the cellular growth and migration phenotypes of cancer cells, establishing a new paradigm to study the biological consequences of HSATII RNA expression, i.e., treatment of normal diploid and tumor cells with DNA-damaging agents.

scholarly journals Control of Cell Proliferation, Organ Growth, and DNA Damage Response Operate Independently of Dephosphorylation of the Arabidopsis Cdk1 Homolog CDKA;1

2009 ◽  
Vol 21 (11) ◽  
pp. 3641-3654 ◽  
Author(s):  
Nico Dissmeyer ◽  
Annika K. Weimer ◽  
Stefan Pusch ◽  
Kristof De Schutter ◽  
Claire Lessa Alvim Kamei ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Organ Growth ◽  
Damage Response

Targeting mTOR by a New Generation of Kinase Inhibitors Sensitizes Leukemia Cells for Chemotherapy Via Suppressing FANCD2 Expression

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1514-1514
Author(s):  
Jie Li ◽  
Fukun Guo ◽  
Jared Sipple ◽  
Sara Kozma ◽  
George Thomas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Cancer Cell ◽  
Dna Damage Response ◽  
Kinase Inhibitor ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Cancer Cell Proliferation ◽  
Damage Response

Abstract Abstract 1514 The mammalian target of rapamycin (mTOR) is a key regulator of nutrient metabolism, cell growth and proliferation. Inhibition of mTOR signaling by rapamycin or rapamycin in combination with antineoplastic agents has been shown to block cancer cell proliferation and cancer angiogenesis. Second-generation pharmacological mTOR inhibitors, which inhibit both mTORC1 and mTORC2 by directly targeting the ATP-binding site of mTOR, have recently shown improved activity in tumor suppression and are under clinical development for cancer therapy. Indeed, it is found that the mTOR kinase inhibitor PP242 inhibits cell proliferation more effectively than rapamycin in pre-clinical models, suggesting the additive contributions of mTORC1 and mTORC2 to cancer cell proliferation and survival. In the present study, we have explored the therapeutic value of PP242 in sensitizing tumor suppression by anti-cancer drugs. We found that the combination of PP242 with Cytarabine (AraC) or Etoposide induced significant higher apoptosis than single-agent treatment in several human lymphoma and leukemia cell lines including K562, Molt-Luc2, and K562-Luc2. Specifically, using Molt-Luc2 cells, the percentages of apoptosis for combined PP242-AraC and PP242-Etoposide treatments were 76.3±4.2% and 78.2+5.9%, respectively, in comparison with 52.7±6.3% and 38.2±4.5%, respectively, in AraC- and Etoposide-treated cells; the basal level of apoptosis in these leukemic cells was 5–8%. Further, PP242, but not Rapamycin, sensitized the leukemia and lymphoma cells to DNA damage induced by AraC or Etoposide, evidenced by a marked increase in g-H2AX foci (94±5% cells in PP242-AraC group vs 25±3% cells in AraC-alone group or 98±4% cells in PP242- Etoposide group vs 36±3% cells in Etoposide-alone group), as well as DNA-strand breaks (comet-tailed value of 25.4±1.2% in PP242-AraC group and 31.2±3.2% in PP242-Etoposide group compared to 9.8±1.2% in AraC-alone and 11.4±2.8% Etoposide-alone groups, respectively). This increased DNA damage response can be attributed to a suppression of the expression of FANCD2, a critical DNA damage repair component of the Fanconi pathway, by PP242, in both normal lymphoblasts and leukemic cells. Significantly, the effect of PP242 on Fanconi gene expression was FANCD2-specific as PP242 had no effect on the expression of other Fanconi proteins such as FANCA and FANCC, and forced expression of FANCD2 by a viral promoter completely abolished the sensitizing effect of PP242 on drug-induced leukemia cell death. We are currently using a mouse xenotransplant model to explore the in vivo effect of the combination of PP242 with AraC for human leukemia cells. Our findings suggest that the mTOR kinase inhibitor PP242 enhances antitumor activity of conventional chemo-drugs by suppressing FANCD2 and associated DNA damage response and consequently augmenting DNA damage leading to apoptosis. Therefore, PP242 combined with chemotherapy could represent a novel strategy for the treatment of hematopoietic malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47phox

2020 ◽  
Vol 117 (46) ◽  
pp. 28806-28815
Author(s):  
Christos Polytarchou ◽  
Maria Hatziapostolou ◽  
Tung On Yau ◽  
Niki Christodoulou ◽  
Philip W. Hinds ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Nadph Oxidase ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Phosphorylation Site ◽  
Ros Scavenging ◽  
Akt Isoforms ◽  
Damage Response ◽  
Inhibit Cell Proliferation

Akt activation up-regulates the intracellular levels of reactive oxygen species (ROS) by inhibiting ROS scavenging. Of the Akt isoforms, Akt3 has also been shown to up-regulate ROS by promoting mitochondrial biogenesis. Here, we employ a set of isogenic cell lines that express different Akt isoforms, to show that the most robust inducer of ROS is Akt3. As a result, Akt3-expressing cells activate the DNA damage response pathway, express high levels of p53 and its direct transcriptional target miR-34, and exhibit a proliferation defect, which is rescued by the antioxidantN-acetylcysteine. The importance of the DNA damage response in the inhibition of cell proliferation by Akt3 was confirmed by Akt3 overexpression inp53−/−andINK4a−/−/Arf−/−mouse embryonic fibroblasts (MEFs), which failed to inhibit cell proliferation, despite the induction of high levels of ROS. The induction of ROS by Akt3 is due to the phosphorylation of the NADPH oxidase subunit p47phox, which results in NADPH oxidase activation. Expression of Akt3 inp47phox−/−MEFs failed to induce ROS and to inhibit cell proliferation. Notably, the proliferation defect was rescued by wild-type p47phox, but not by the phosphorylation site mutant of p47phox. In agreement with these observations, Akt3 up-regulates p53 in human cancer cell lines, and the expression of Akt3 positively correlates with the levels of p53 in a variety of human tumors. More important,Akt3alterations correlate with a higher frequency of mutation ofp53, suggesting that tumor cells may adapt to high levels of Akt3, by inactivating the DNA damage response.

scholarly journals Werner syndrome protein (WRN) regulates cell proliferation and the human papillomavirus 16 life cycle during epithelial differentiation

2020 ◽  
Author(s):  
Claire D. James ◽  
Dipon Das ◽  
Ethan L. Morgan ◽  
Raymonde Otoa ◽  
Andrew Macdonald ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Life Cycle ◽  
Dna Replication ◽  
Viral Replication ◽  
Dna Damage Response ◽  
Basal Cell ◽  
Viral Life Cycle ◽  
Cervical Lesions ◽  
Damage Response

AbstractHuman papillomaviruses recruit a host of DNA damage response factors to their viral genome to facilitate homologous recombination replication in association with the viral replication factors E1 and E2. We previously demonstrated that SIRT1 deacetylation of WRN promotes recruitment of WRN to E1-E2 replicating DNA, and that WRN regulates both the levels and fidelity of E1-E2 replication. The deacetylation of WRN by SIRT1 results in an active protein able to complex with replicating DNA, but a protein that is less stable. Here we demonstrate an inverse correlation between SIRT1 and WRN in CIN cervical lesions when compared with normal control tissue, supporting our model of SIRT1 deacetylation destabilizing WRN protein. We CRISPR/Cas9 edited N/Tert-1 and N/Tert-1+HPV16 cells to knock out WRN protein expression and subjected the cells to organotypic raft cultures. In N/Tert-1 cells without WRN expression there was enhanced basal cell proliferation, DNA damage and thickening of the differentiated epithelium. In N/Tert-1+HPV16 cells, there was enhanced basal cell proliferation, increased DNA damage throughout the epithelium and increased viral DNA replication. Overall, the results demonstrate that the expression of WRN is required to control the proliferation of N/Tert-1 cells and controls the HPV16 life cycle in these cells. This complements our previous data demonstrating that WRN controls the levels and fidelity of HPV16 E1-E2 DNA replication. The results describe a new role for WRN, a tumor suppressor, in controlling keratinocyte differentiation and the HPV16 life cycle.ImportanceHPV16 is the major human viral carcinogen, responsible for around 3-4% of all cancers worldwide. Our understanding of how the viral replication machinery interacts with host factors to control/activate the DNA damage response to promote the viral life cycle remains incomplete. Recently, we demonstrated a SIRT1-WRN axis that controls HPV16 replication and here we demonstrate that this axis persists in clinical cervical lesions induced by HPV16. Here we describe the effects of WRN depletion on cellular differentiation with and without HPV16; WRN depletion results in enhanced proliferation and DNA damage irrespective of HPV16 status. Also, WRN is a restriction factor for the viral life cycle as replication is disrupted in the absence of WRN. Future studies will focus on enhancing our understanding of how WRN regulates viral replication. Our goal is to ultimately identify cellular factors essential for HPV16 replication that can be targeted for therapeutic gain.

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