scholarly journals The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells

2015 ◽  
Vol 172 (9) ◽  
pp. 2246-2257 ◽  
Author(s):  
Shiwei Deng ◽  
Tiandong Yan ◽  
Teodora Nikolova ◽  
Dominik Fuhrmann ◽  
Andrea Nemecek ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Topoisomerase Ii ◽  
Dna Breaks ◽  
Topoisomerase Ii Inhibitor ◽  
Damage Response

scholarly journals HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marie-France Langelier ◽  
Ramya Billur ◽  
Aleksandr Sverzhinsky ◽  
Ben E. Black ◽  
John M. Pascal
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Chain Elongation ◽  
Dna Breaks ◽  
Data Support ◽  
Damage Response ◽  
Hit And Run ◽  
Dna Break ◽  
Structural Insights ◽  
In Cells

AbstractPARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, PARP1 is substantially more abundant in cells than HPF1, challenging whether HPF1 can pervasively modulate PARP1. Here, we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates/dissociates from multiple PARP1 molecules, initiating serine modification before modification initiates on glutamate/aspartate, and accelerating initiation to be more comparable to elongation reactions forming poly(ADP-ribose). This “hit and run” mechanism ensures HPF1 contributions to PARP1/2 during initiation do not persist and interfere with PAR chain elongation. We provide structural insights into HPF1/PARP1 assembled on a DNA break, and assess HPF1 impact on PARP1 retention on DNA. Our data support the prevalence of serine-ADP-ribose modification in cells and the efficiency of serine-ADP-ribose modification required for an acute DNA damage response.

scholarly journals APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Md Akram Hossain ◽  
Yunfeng Lin ◽  
Garrett Driscoll ◽  
Jia Li ◽  
Anne McMahon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Human Pancreatic Cancer ◽  
Genome Integrity ◽  
Pancreatic Cancer Cells ◽  
Damage Response ◽  
Egg Extracts

The maintenance of genome integrity and fidelity is vital for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required to activate an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of the DDR pathway in mammalian cells. Here, we provide evidence using human pancreatic cancer cells that APE2 is essential for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knockdown (KD) leads to enhanced γH2AX foci and increased micronuclei formation. In addition, we identified a small molecule compound Celastrol as an APE2 inhibitor that specifically compromises the binding of APE2 but not RPA to ssDNA and 3′-5′ exonuclease activity of APE2 but not APE1. The impairment of ATR-Chk1 DDR pathway by Celastrol in Xenopus egg extracts and human pancreatic cancer cells highlights the physiological significance of Celastrol in the regulation of APE2 functionalities in genome integrity. Notably, cell viability assays demonstrate that APE2-KD or Celastrol sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, we propose APE2 as a general regulator for the DDR pathway in genome integrity maintenance.

scholarly journals Role of the circadian clock "Death-Loop" in the DNA damage response underpinning cancer treatment resistance

2022 ◽  
Author(s):  
Ninel Miriam Vainshelbaum ◽  
Kristine Salmina ◽  
Bogdan I Gerashchenko ◽  
Marija Lazovska ◽  
Pawel Zayakin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Circadian Clock ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Embryonic Stem ◽  
Early Embryo ◽  
Mitotic Slippage ◽  
Damage Response ◽  
Telomere Regulation

The Circadian Clock (CC) drives the normal cell cycle and reciprocally regulates telomere elongation. However, it can be deregulated in cancer, embryonic stem cells (ESC) and the early embryo. Here, its role in the resistance of cancer cells to genotoxic treatments was assessed in relation to whole-genome duplication (WGD) and telomere regulation. We first evaluated the DNA damage response of polyploid cancer cells and observed a similar impact on the cell cycle to that seen in ESC - overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, and coupling telomere erosion to accelerated cell senescence, favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Next, we revealed a positive correlation between cancer WGD and deregulation of CC assessed by bioinformatics on 11 primary cancer datasets (rho=0.83; p<0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by recombination and return their depolyploidised mitotic offspring to TERT-dependent telomere regulation. Through depolyploidisation and the CC "death loop", the telomeres and Hayflick limit count are thus again renewed. This mechanism along with similar inactivity of the CC in early embryos supports a life-cycle (embryonic) concept of cancer.

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