scholarly journals DNA damage response activated by anti-cancer agent, irofulven

2007 ◽  
Author(s):  
Timothy D. Wiltshire
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Anti Cancer ◽  
Damage Response ◽  
Cancer Agent

scholarly journals Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

Open Biology ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 140156 ◽  
Author(s):  
Didier J. Colin ◽  
Karolina O. Hain ◽  
Lindsey A. Allan ◽  
Paul R. Clarke
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinases ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Anti Cancer ◽  
Damage Response ◽  
Microtubule Poisons

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

Breaking the DNA Damage Response via Serine/Threonine Kinase Inhibitors to Improve Cancer Treatment

2019 ◽  
Vol 26 (8) ◽  
pp. 1425-1445 ◽  
Author(s):  
Wioletta Rozpędek ◽  
Dariusz Pytel ◽  
Alicja Nowak-Zduńczyk ◽  
Dawid Lewko ◽  
Radosław Wojtczak ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Kinase Inhibitors ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Anti Cancer ◽  
Damage Response

Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/ threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death. Interestingly, key components of DDR signaling networks may constitute an attractive target for anti-cancer therapy through two distinct potential approaches: as chemoand radiosensitizers to enhance the effectiveness of currently used genotoxic treatment or as single agents to exploit defects in DDR in cancer cells via synthetic lethal approach. Moreover, the newest data reported that serine/threonine protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is also closely associated with cancer development and progression. Thereby, utilization of small-molecule, serine/threonine kinase inhibitors may provide a novel, groundbreaking, anti-cancer treatment strategy. Currently, a range of potent, highlyselective toward ATM, ATR and PERK inhibitors has been discovered, but after foregoing study, additional investigations are necessary for their future clinical use.

scholarly journals Anti-cancer drug KP1019 modulates epigenetics and induces DNA damage response inSaccharomyces cerevisiae

FEBS Letters ◽  
2014 ◽  
Vol 588 (6) ◽  
pp. 1044-1052 ◽  
Author(s):  
Vikash Singh ◽  
Gajendra Kumar Azad ◽  
Papita Mandal ◽  
M. Amarendar Reddy ◽  
Raghuvir S. Tomar
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Drug ◽  
Anti Cancer ◽  
Damage Response

T1197 DNA Damage Response in Aberrant Crypt Foci of Radiation Colitis as a Anti-Cancer Barrier in Early Tumorigenesis

2010 ◽  
Vol 138 (5) ◽  
pp. S-509
Author(s):  
Kazuko Shichijo ◽  
Makoto Ihara ◽  
Shiro Miura ◽  
Tomomi Kurashige ◽  
Mutsumi M. Matsuyama ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Aberrant Crypt Foci ◽  
Anti Cancer ◽  
Damage Response ◽  
Radiation Colitis

scholarly journals Autophagic Organelles in DNA Damage Response

2021 ◽  
Vol 9 ◽  
Author(s):  
Jeongha Kim ◽  
Sungmin Lee ◽  
Hyunwoo Kim ◽  
Haksoo Lee ◽  
Ki Moon Seong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Cellular Homeostasis ◽  
Dna Damaging Agents ◽  
Anti Cancer ◽  
Damage Response ◽  
Cargo Proteins ◽  
Cellular Stresses ◽  
Key Events

Autophagy is an important subcellular event engaged in the maintenance of cellular homeostasis via the degradation of cargo proteins and malfunctioning organelles. In response to cellular stresses, like nutrient deprivation, infection, and DNA damaging agents, autophagy is activated to reduce the damage and restore cellular homeostasis. One of the responses to cellular stresses is the DNA damage response (DDR), the intracellular pathway that senses and repairs damaged DNA. Proper regulation of these pathways is crucial for preventing diseases. The involvement of autophagy in the repair and elimination of DNA aberrations is essential for cell survival and recovery to normal conditions, highlighting the importance of autophagy in the resolution of cell fate. In this review, we summarized the latest information about autophagic recycling of mitochondria, endoplasmic reticulum (ER), and ribosomes (called mitophagy, ER-phagy, and ribophagy, respectively) in response to DNA damage. In addition, we have described the key events necessary for a comprehensive understanding of autophagy signaling networks. Finally, we have highlighted the importance of the autophagy activated by DDR and appropriate regulation of autophagic organelles, suggesting insights for future studies. Especially, DDR from DNA damaging agents including ionizing radiation (IR) or anti-cancer drugs, induces damage to subcellular organelles and autophagy is the key mechanism for removing impaired organelles.

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