scholarly journals A Tale of Ice and Fire: The Dual Role for 17β-Estradiol in Balancing DNA Damage and Genome Integrity

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1583
Author(s):  
Sara Pescatori ◽  
Francesco Berardinelli ◽  
Jacopo Albanesi ◽  
Paolo Ascenzi ◽  
Maria Marino ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Transformation ◽  
Genome Integrity ◽  
Physiological Effects ◽  
Dna Damages ◽  
Cellular Effects ◽  
Damage Response ◽  
17Β Estradiol ◽  
Cellular Pathways ◽  
Definition Of

17β-estradiol (E2) regulates human physiology both in females and in males. At the same time, E2 acts as a genotoxic substance as it could induce DNA damages, causing the initiation of cellular transformation. Indeed, increased E2 plasma levels are a risk factor for the development of several types of cancers including breast cancer. This paradoxical identity of E2 undermines the foundations of the physiological definition of “hormone” as E2 works both as a homeostatic regulator of body functions and as a genotoxic compound. Here, (i) the molecular circuitries underlying this double face of E2 are reviewed, and (ii) a possible framework to reconcile the intrinsic discrepancies of the E2 function is reported. Indeed, E2 is a regulator of the DNA damage response, which this hormone exploits to calibrate its genotoxicity with its physiological effects. Accordingly, the genes required to maintain genome integrity belong to the E2-controlled cellular signaling network and are essential for the appearance of the E2-induced cellular effects. This concept requires an “upgrade” to the vision of E2 as a “genotoxic hormone”, which balances physiological and detrimental pathways to guarantee human body homeostasis. Deregulation of this equilibrium between cellular pathways would determine the E2 pathological effects.

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 Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

2018 ◽  
Vol 19 (8) ◽  
pp. 2389 ◽  
Author(s):  
Md. Hossain ◽  
Yunfeng Lin ◽  
Shan Yan
Keyword(s):  
Dna Damage ◽  
Genome Instability ◽  
Strand Break ◽  
Single Strand ◽  
Genome Integrity ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Damage Response ◽  
End Resection

DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity.

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 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 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 Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells

2010 ◽  
Vol 24 (6) ◽  
pp. 424-435 ◽  
Author(s):  
Bo Cui ◽  
Stewart P. Johnson ◽  
Nancy Bullock ◽  
Francis Ali-Osman ◽  
Darell D. Bigner ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Glioblastoma Cells ◽  
Dna Damages ◽  
Damage Response

scholarly journals Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation

2020 ◽  
Author(s):  
Kalaiyarasi Ragunathan ◽  
Nikki Lyn Esnardo Upfold ◽  
Valentyn Oksenych
Keyword(s):  
Dna Damage ◽  
Tumor Microenvironment ◽  
Ionizing Radiation ◽  
Immune Cells ◽  
Mammalian Cells ◽  
Cancer Associated Fibroblasts ◽  
Cell Type ◽  
Dna Damages ◽  
Damage Response ◽  
High Doses

Cancer-associated fibroblasts (CAF) form the basis of tumor microenvironment and possess immunomodulatory functions by interacting with other cells surrounding tumor, including T lymphocytes, macrophages, dendritic cells and natural killer cells. Ionizing radiation is a broadly-used method in radiotherapy to target tumors. In mammalian cells, ionizing radiation induces various types of DNA damages and DNA damage response. Being unspecific, radiotherapy affects all the cells in tumor microenvironment, including the tumor itself, CAFs and immune cells. CAFs are extremely radio-resistant and do not initiate apoptosis even at high doses of radiation. However, following radiation, CAFs become senescent and produce a distinct combination of immunoregulatory molecules. Radiosensitivity of immune cells varies depending on the cell type due to inefficient DNA repair in, for example, monocytes and granulocytes. In this minireview, we are summarizing recent findings on the interaction between CAF, ionizing radiation and immune cells in the tumor microenvironment.

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.

Sign in / Sign up

Export Citation Format

Share Document