scholarly journals Bcl2 Induces DNA Replication Stress by Inhibiting Ribonucleotide Reductase

2013 ◽  
Vol 74 (1) ◽  
pp. 212-223 ◽  
Author(s):  
Maohua Xie ◽  
Yun Yen ◽  
Taofeek K. Owonikoko ◽  
Suresh S. Ramalingam ◽  
Fadlo R. Khuri ◽  
...  
Keyword(s):  
Dna Replication ◽  
Ribonucleotide Reductase ◽  
Replication Stress ◽  
Dna Replication Stress

Ribonucleotide reductase from Fusarium oxysporum does not Respond to DNA replication stress

DNA Repair ◽  
2019 ◽  
Vol 83 ◽  
pp. 102674 ◽  
Author(s):  
Rotem Cohen ◽  
Shira Milo ◽  
Sushma Sharma ◽  
Alon Savidor ◽  
Shay Covo
Keyword(s):  
Dna Replication ◽  
Fusarium Oxysporum ◽  
Ribonucleotide Reductase ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2520
Author(s):  
Alexandra Nguyen ◽  
Melanie Dzulko ◽  
Janine Murr ◽  
Yun Yen ◽  
Günter Schneider ◽  
...  
Keyword(s):  
Dna Replication ◽  
Ribonucleotide Reductase ◽  
Ataxia Telangiectasia ◽  
Replication Stress ◽  
Ductal Adenocarcinoma ◽  
Ataxia Telangiectasia Mutated ◽  
Pancreatic Cancer Cells ◽  
Dismal Prognosis ◽  
Class 1 ◽  
Dna Replication Stress

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a dismal prognosis. Here, we show how an inhibition of de novo dNTP synthesis by the ribonucleotide reductase (RNR) inhibitor hydroxyurea and an inhibition of epigenetic modifiers of the histone deacetylase (HDAC) family affect short-term cultured primary murine PDAC cells. We used clinically relevant doses of hydroxyurea and the class 1 HDAC inhibitor entinostat. We analyzed the cells by flow cytometry and immunoblot. Regarding the induction of apoptosis and DNA replication stress, hydroxyurea and the novel RNR inhibitor COH29 are superior to the topoisomerase-1 inhibitor irinotecan which is used to treat PDAC. Entinostat promotes the induction of DNA replication stress by hydroxyurea. This is associated with an increase in the PP2A subunit PR130/PPP2R3A and a reduction of the ribonucleotide reductase subunit RRM2 and the DNA repair protein RAD51. We further show that class 1 HDAC activity promotes the hydroxyurea-induced activation of the checkpoint kinase ataxia-telangiectasia mutated (ATM). Unlike in other cell systems, ATM is pro-apoptotic in hydroxyurea-treated murine PDAC cells. These data reveal novel insights into a cytotoxic, ATM-regulated, and HDAC-dependent replication stress program in PDAC cells.

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.

scholarly journals MCM10 compensates for Myc‐induced DNA replication stress in breast cancer stem‐like cells

2020 ◽  
Author(s):  
Takahiko Murayama ◽  
Yasuto Takeuchi ◽  
Kaoru Yamawaki ◽  
Toyoaki Natsume ◽  
Li Mengjiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Replication ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals MTA2 sensitizes gastric cancer cells to PARP inhibition by induction of DNA replication stress

2021 ◽  
Vol 14 (10) ◽  
pp. 101167
Author(s):  
Jinwen Shi ◽  
Xiaofeng Zhang ◽  
Jin'e Li ◽  
Wenwen Huang ◽  
Yini Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Replication Stress ◽  
Parp Inhibition ◽  
Gastric Cancer Cells ◽  
Dna Replication Stress
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