scholarly journals The Role of the Transcriptional Response to DNA Replication Stress

Genes ◽  
2017 ◽  
Vol 8 (3) ◽  
pp. 92 ◽  
Author(s):  
Anna Herlihy ◽  
Robertus de Bruin
Keyword(s):  
Dna Replication ◽  
Transcriptional Response ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals A role of the mitotic spindle checkpoint in the cellular response to DNA replication stress

2006 ◽  
Vol 99 (3) ◽  
pp. 759-769 ◽  
Author(s):  
Anette Duensing ◽  
Xiaoyi Teng ◽  
Ying Liu ◽  
Michelle Tseng ◽  
Nicole Spardy ◽  
...  
Keyword(s):  
Dna Replication ◽  
Mitotic Spindle ◽  
Cellular Response ◽  
Spindle Checkpoint ◽  
Replication Stress ◽  
Mitotic Spindle Checkpoint ◽  
Dna Replication Stress

scholarly journals Role of a Candida albicans Nrm1/Whi5 homologue in cell cycle gene expression and DNA replication stress response

2012 ◽  
Vol 84 (4) ◽  
pp. 778-794 ◽  
Author(s):  
Ayala Ofir ◽  
Kay Hofmann ◽  
Esther Weindling ◽  
Tsvia Gildor ◽  
Katherine S. Barker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Candida Albicans ◽  
Dna Replication ◽  
Stress Response ◽  
Replication Stress ◽  
Cell Cycle Gene ◽  
Dna Replication Stress ◽  
Cell Cycle Gene Expression

scholarly journals APOBEC3B Is Induced By Activation of DNA Repair Pathway and Modulates the Survival and Treatment Response in Human Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 407-407 ◽  
Author(s):  
Lijie Xing ◽  
Jiye Liu ◽  
Liang Lin ◽  
Shih-Feng Cho ◽  
Kenneth Wen ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cell Lines ◽  
Drug Sensitivity ◽  
Replication Stress ◽  
Growth And Survival ◽  
Dna Replication Stress ◽  
Equity Ownership ◽  
Lethal Doses

Abstract Constitutive genomic complexity, ongoing DNA damage, and accumulating mutations are observed with progression from monoclonal gammopathy of undetermined significance (MGUS) to active multiple myeloma (MM) to relapsed/refractory disease. Apolipoprotein B mRNA editing catalytic polypeptide-like 3B (APOBEC3B), a DNA cytosine deaminase, plays a prominent role in inducing mutations in multiple human cancers. In MM, APOBEC3B is linked to sub-clonal diversification, intra-tumor heterogeneity, and tumor evolution. Moreover, upregulation of APOBEC3B is associated with poor MM prognosis, suggesting that targeting MM cells with high APOBEC3B may represent a novel therapeutic approach. We here studied the upstream mechanisms of APOBEC3B dysregulation and further defined functional consequences of molecular manipulation of APOBEC3B in MM cells. We characterized its sequelae to identify novel strategies for cancer prevention or treatment by targeting this key driver gene of cancer mutagenesis. Since the expression of APOBEC3B is associated with replication stress in breast cancer, we first asked whether APOBEC3B levels are altered in MM cell lines upon treatments with Melphalan (Mel), an alkylating agent used to treat MM which is known to induce replication stress; or with ionizing radiation (IR). Using quantitative RT-PCR and Western blotting, we found that sub-lethal doses of Mel or IR induce APOBEC3B expression in a dose- and time-dependent manner in MM cell lines (n=7) associated with the phosphorylation of γH2AX. Interestingly bortezomib (btz), even at sub-lethal doses which triggers DNA damage signaling, also induced APOBEC3B expression in H929, MM1S, and U266 MM cells. Since DNA replication stress activates the ATR/ATM pathway, we next investigated whether these kinases mediate APOBEC3B induction following Mel- or IR- or btz-induced DNA replication stress. H929 and MM1S cells were treated with Mel or IR in the presence or absence of ATM or ATR inhibitors, and these cells were then lysed and assayed for APOBEC3B expression. Importantly, inhibition of ATR or ATM activation pathway significantly decreased Mel- or IR or btz-induced APOBEC3B, suggesting that replication stress induced by Mel, IR, or btz, activates transcription of APOBEC3B via an ATM/ATR dependent pathway in vitro. To test the effect of APOBEC3B on cell growth and survival, we used gene-specific CRISPR knock out (KO), shRNA knockdown (KD), and inducible-shRNA KD to study the functional impact of perturbation of APOBEC3B in MM cells. Both KO and KD of APOBEC3B decreased growth and survival in multiple MM cell lines sensitive or resistant to dexamethasone or lenalidomide. Using zombie aqua and annexin V-based flow cytometric analysis, we showed that APOBEC3B inhibition enhanced growth arrest, followed by apoptosis, in these MM cells. These data suggest an important role of increased APOBEC3B levels in MM cell survival. We next analyzed available data sources for MM cell lines from Cancer Cell Line Encyclopedia (CCLE) and the Genomics of Drug Sensitivity in Cancer (GDSC), which include microarray gene expression and drug sensitivity information. APOBEC3B expression negatively correlates with MM cell sensitivity to JQ1, a BET inhibitor which has been reported to inhibit MM cell growth and survival in vitro and in vivo. Importantly, in MM cell lines which are relatively resistant to pomalidomide and JQ1 than other cell lines, APOBEC3B KD by its shRNA enhances sensitivity to both drugs. Taken together, our findings provide new insights into the role of APOBEC3B in triggering cytidine deaminase-induced mutagenesis associated with progression of disease. Furthermore, we show that DNA replication stress triggered by Mel, IR, or btz upregulates APOBEC3B expression, which in turn confers drug resistance. The role of APOBEC in disease pathogenesis and progression, coupled with its role mediating drug resistance, suggest potential utility of targeting APOBEC in novel MM therapies. Disclosures Munshi: OncoPep: Other: Board of director. Anderson:Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy; Celgene: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Gilead: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Targeting DNA Replication Stress for Cancer Therapy

Genes ◽  
2016 ◽  
Vol 7 (8) ◽  
pp. 51 ◽  
Author(s):  
Jun Zhang ◽  
Qun Dai ◽  
Dongkyoo Park ◽  
Xingming Deng
Keyword(s):  
Dna Replication ◽  
Cancer Therapy ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals Targeting the DNA replication stress phenotype of KRAS mutant cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tara Al Zubaidi ◽  
O. H. Fiete Gehrisch ◽  
Marie-Michelle Genois ◽  
Qi Liu ◽  
Shan Lu ◽  
...  
Keyword(s):  
Dna Replication ◽  
Single Molecule ◽  
Replication Stress ◽  
Proton Radiation ◽  
Wild Type ◽  
Cellular Effects ◽  
Proton Treatment ◽  
Dna Replication Stress ◽  
Fork Stalling ◽  
Mutant Cells

AbstractMutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.

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