scholarly journals PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response

2017 ◽  
Vol 67 (2) ◽  
pp. 266-281.e4 ◽  
Author(s):  
Elisa Ferrari ◽  
Christopher Bruhn ◽  
Marta Peretti ◽  
Corinne Cassani ◽  
Walter Vincenzo Carotenuto ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Metabolic Pathways ◽  
Nutrient Sensing ◽  
Genome Integrity ◽  
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 Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2051 ◽  
Author(s):  
Amandine Moretton ◽  
Joanna I. Loizou
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Metabolic Regulation ◽  
Current Knowledge ◽  
Cellular Metabolism ◽  
Genome Integrity ◽  
Cancer Treatments ◽  
Damage Response ◽  
Dynamic Interplay ◽  
Remarkable Progress

Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.

scholarly journals Inactivating UBE2M Impacts the DNA Damage Response and Genome Integrity Involving Multiple Cullin Ligases

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e101844 ◽  
Author(s):  
Scott Cukras ◽  
Nicholas Morffy ◽  
Takbum Ohn ◽  
Younghoon Kee
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Integrity ◽  
Damage Response

scholarly journals The Nup84 complex coordinates the DNA damage response to warrant genome integrity

2019 ◽  
Vol 47 (8) ◽  
pp. 4054-4067 ◽  
Author(s):  
Hélène Gaillard ◽  
José M Santos-Pereira ◽  
Andrés Aguilera
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Integrity ◽  
Damage Response

scholarly journals Autophagy Roles in Genome Maintenance

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1793 ◽  
Author(s):  
Susanna Ambrosio ◽  
Barbara Majello
Keyword(s):  
Dna Damage ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Current Knowledge ◽  
Response To Therapy ◽  
Genome Integrity ◽  
Genome Maintenance ◽  
Damage Response ◽  
Cancer Cell Survival ◽  
Fate Decision

In recent years, a considerable correlation has emerged between autophagy and genome integrity. A range of mechanisms appear to be involved where autophagy participates in preventing genomic instability, as well as in DNA damage response and cell fate decision. These initial findings have attracted particular attention in the context of malignancy; however, the crosstalk between autophagy and DNA damage response is just beginning to be explored and key questions remain that need to be addressed, to move this area of research forward and illuminate the overall consequence of targeting this process in human therapies. Here we present current knowledge on the complex crosstalk between autophagy and genome integrity and discuss its implications for cancer cell survival and response to therapy.

Chemical strategies for development of ATR inhibitors

2014 ◽  
Vol 16 ◽  
Author(s):  
Sabin Llona-Minguez ◽  
Andreas Höglund ◽  
Sylvain A. Jacques ◽  
Tobias Koolmeister ◽  
Thomas Helleday
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Checkpoint Inhibitors ◽  
Genome Integrity ◽  
Signalling Pathways ◽  
Replication Forks ◽  
Damage Response ◽  
Key Players ◽  
Chemical Strategies ◽  
Stalled Replication Forks

ATR protein kinase is one of the key players in maintaining genome integrity and coordinating of the DNA damage response and repair signalling pathways. Inhibition of ATR prevents signalling from stalled replication forks and enhances the formation of DNA damage, particularly under conditions of replication stress present in cancers. For this reason ATR/CHK1 checkpoint inhibitors can potentiate the effect of DNA cross-linking agents, as evidenced by ATR inhibitors recently entering human clinical trials. This review aims to compile the existing literature on small molecule inhibitors of ATR, both from academia and the pharmaceutical industry, and will provide the reader with a comprehensive summary of this promising oncology target.

scholarly journals Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding

2008 ◽  
Vol 83 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Jennifer Hein ◽  
Sergei Boichuk ◽  
Jiaping Wu ◽  
Yuan Cheng ◽  
Raimundo Freire ◽  
...  
Keyword(s):  
Dna Damage ◽  
Viral Replication ◽  
Dna Damage Response ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Genome Integrity ◽  
Large T Antigen ◽  
Sv40 Large T Antigen ◽  
Damage Response

ABSTRACT Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shown to lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of γ-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.

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