scholarly journals Targeting cancer using KAT inhibitors to mimic lethal knockouts

2016 ◽  
Vol 44 (4) ◽  
pp. 979-986 ◽  
Author(s):  
James A.L. Brown ◽  
Emer Bourke ◽  
Leif A. Eriksson ◽  
Michael J. Kerin
Keyword(s):  
Dna Damage Response ◽  
Treatment Options ◽  
Histone Acetyltransferases ◽  
Genome Maintenance ◽  
Cancer Treatments ◽  
Essential Protein ◽  
Hat Superfamily ◽  
Damage Response ◽  
New Treatment ◽  
Target Effects

Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate). In the present study we focus on the development of lysine (K) acetyltransferase inhibitors (KATi) targeting the MYST family member Tip60 (Kat5), an essential protein, designed or discovered through screening libraries. Importantly, Tip60 has been demonstrated to be significantly down-regulated in many cancers which urgently require new treatment options. We highlight current and future efforts employing these KATi as cancer treatments and their ability to synergize and enhance current cancer treatments. We investigate the different methods of KATi production or discovery, their mechanisms and their validation models. Importantly, the utility of KATi is based on a key concept: using KATi to abrogate the activity of an already down-regulated essential protein (effectively creating a lethal knockout) provides another innovative mechanism for targeting cancer cells, while significantly minimizing any off-target effects to normal cells. This approach, combined with the rapidly developing interest in KATi, suggests that KATi have a bright future for providing truly personalized therapies.

scholarly journals Overall Cdk activity modulates the DNA damage response in mammalian cells

2009 ◽  
Vol 187 (6) ◽  
pp. 773-780 ◽  
Author(s):  
Antonio Cerqueira ◽  
David Santamaría ◽  
Bárbara Martínez-Pastor ◽  
Miriam Cuadrado ◽  
Oscar Fernández-Capetillo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Cyclin Dependent Kinase ◽  
Genome Maintenance ◽  
Cycle Progression ◽  
Damage Response ◽  
Dna Break ◽  
Specific Contribution

In response to DNA damage, cells activate a phosphorylation-based signaling cascade known as the DNA damage response (DDR). One of the main outcomes of DDR activation is inhibition of cyclin-dependent kinase (Cdk) activity to restrain cell cycle progression until lesions are healed. Recent studies have revealed a reverse connection by which Cdk activity modulates processing of DNA break ends and DDR activation. However, the specific contribution of individual Cdks to this process remains poorly understood. To address this issue, we have examined the DDR in murine cells carrying a defined set of Cdks. Our results reveal that genome maintenance programs of postreplicative cells, including DDR, are regulated by the overall level of Cdk activity and not by specific Cdks.

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 An Insight Into the Mechanism of Plant Organelle Genome Maintenance and Implications of Organelle Genome in Crop Improvement: An Update

2021 ◽  
Vol 9 ◽  
Author(s):  
Kalyan Mahapatra ◽  
Samrat Banerjee ◽  
Sayanti De ◽  
Mehali Mitra ◽  
Pinaki Roy ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Crop Improvement ◽  
Nuclear Genome ◽  
Genome Maintenance ◽  
Organelle Genome ◽  
Organellar Genomes ◽  
Damage Repair ◽  
Damage Response ◽  
Repair Pathways

Besides the nuclear genome, plants possess two small extra chromosomal genomes in mitochondria and chloroplast, respectively, which contribute a small fraction of the organelles’ proteome. Both mitochondrial and chloroplast DNA have originated endosymbiotically and most of their prokaryotic genes were either lost or transferred to the nuclear genome through endosymbiotic gene transfer during the course of evolution. Due to their immobile nature, plant nuclear and organellar genomes face continuous threat from diverse exogenous agents as well as some reactive by-products or intermediates released from various endogenous metabolic pathways. These factors eventually affect the overall plant growth and development and finally productivity. The detailed mechanism of DNA damage response and repair following accumulation of various forms of DNA lesions, including single and double-strand breaks (SSBs and DSBs) have been well documented for the nuclear genome and now it has been extended to the organelles also. Recently, it has been shown that both mitochondria and chloroplast possess a counterpart of most of the nuclear DNA damage repair pathways and share remarkable similarities with different damage repair proteins present in the nucleus. Among various repair pathways, homologous recombination (HR) is crucial for the repair as well as the evolution of organellar genomes. Along with the repair pathways, various other factors, such as the MSH1 and WHIRLY family proteins, WHY1, WHY2, and WHY3 are also known to be involved in maintaining low mutation rates and structural integrity of mitochondrial and chloroplast genome. SOG1, the central regulator in DNA damage response in plants, has also been found to mediate endoreduplication and cell-cycle progression through chloroplast to nucleus retrograde signaling in response to chloroplast genome instability. Various proteins associated with the maintenance of genome stability are targeted to both nuclear and organellar compartments, establishing communication between organelles as well as organelles and nucleus. Therefore, understanding the mechanism of DNA damage repair and inter compartmental crosstalk mechanism in various sub-cellular organelles following induction of DNA damage and identification of key components of such signaling cascades may eventually be translated into strategies for crop improvement under abiotic and genotoxic stress conditions. This review mainly highlights the current understanding as well as the importance of different aspects of organelle genome maintenance mechanisms in higher plants.

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.

Structure meets function—Centrosomes, genome maintenance and the DNA damage response

2006 ◽  
Vol 312 (14) ◽  
pp. 2633-2640 ◽  
Author(s):  
Harald Löffler ◽  
Jiri Lukas ◽  
Jiri Bartek ◽  
Alwin Krämer
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Maintenance ◽  
Damage Response

scholarly journals Inhibition of USP28 overcomes Cisplatin-resistance of squamous tumors by suppression of the Fanconi anemia pathway

2021 ◽  
Author(s):  
Cristian Prieto-Garcia ◽  
Oliver Hartmann ◽  
Michaela Reissland ◽  
Thomas Fischer ◽  
Carina R. Maier ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Fanconi Anemia ◽  
Cisplatin Resistance ◽  
Treatment Options ◽  
Chemotherapy Resistance ◽  
Specific Inhibitor ◽  
Platinum Based Chemotherapy ◽  
Damage Response ◽  
Novel Therapeutic Strategies

Abstract Squamous cell carcinomas (SCC) frequently have an exceptionally high mutational burden. As consequence, they rapidly develop resistance to platinum-based chemotherapy and overall survival is limited. Novel therapeutic strategies are therefore urgently required. SCC express ∆Np63, which regulates the Fanconi Anemia (FA) DNA-damage response in cancer cells, thereby contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity. This phosphorylation event is required to positively regulate the DNA damage repair in SCC by stabilizing ∆Np63. Knock-down or inhibition of USP28 by a specific inhibitor weakens the ability of SCC to cope with DNA damage during platin-based chemotherapy. Hence, our study presents a novel mechanism by which ∆Np63 expressing SCC can be targeted to overcome chemotherapy resistance. Limited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ∆Np63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-∆Np63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.

scholarly journals DNMT3A-NPM1 mutated acute myeloid leukaemia shows sensitivity to a PARP1 inhibitor combined with daunorubicin in an in vitro model

2018 ◽  
Author(s):  
Grigore Gafencu ◽  
Valentina Pileczki ◽  
Ancuta Jurj ◽  
Lorand Magdo ◽  
Cristina Selicean ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Damage Response ◽  
Vitro Model ◽  
New Treatment ◽  
Acute Myeloid

SummaryAcute myeloid leukaemia is a neoplasia in need of new treatment approaches. PARP inhibitors are a class of targeted therapeutics for cancer that disrupts dysfunctional DNA damage response in various neoplasia. MLL-AF9 mutated leukaemias are sensitive to combinations of PARP inhibitors and cytotoxic drugs. Moreover, DNMT3A and NPM1 mutations are linked to dysfunctions in DNA damage response. Therefore, we investigated if DNMT3A-NPM1 mutated AML cell line is sensible to PARP inhibitors combined with anthracyclines. Our results show that DNMT3A-NPM1 mutated AML is as sensible to combinations of PARP inhibitors and anthracyclines as MLL-AF9 mutated leukaemias, in an in vitro setting.

scholarly journals ATR signalling: more than meeting at the fork

2011 ◽  
Vol 436 (3) ◽  
pp. 527-536 ◽  
Author(s):  
Edward A. Nam ◽  
David Cortez
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Protein Interactions ◽  
Cell Cycle Checkpoints ◽  
Protein Protein Interactions ◽  
Genome Maintenance ◽  
Origin Firing ◽  
Damage Response ◽  
Dna Replication Origin

Preservation of genome integrity via the DNA-damage response is critical to prevent disease. ATR (ataxia telangiectasia mutated- and Rad3-related) is essential for life and functions as a master regulator of the DNA-damage response, especially during DNA replication. ATR controls and co-ordinates DNA replication origin firing, replication fork stability, cell cycle checkpoints and DNA repair. Since its identification 15 years ago, a model of ATR activation and signalling has emerged that involves localization to sites of DNA damage and activation through protein–protein interactions. Recent research has added an increasingly detailed understanding of the canonical ATR pathway, and an appreciation that the canonical model does not fully capture the complexity of ATR regulation. In the present article, we review the ATR signalling process, focusing on mechanistic findings garnered from the identification of new ATR-interacting proteins and substrates. We discuss how to incorporate these new insights into a model of ATR regulation and point out the significant gaps in our understanding of this essential genome-maintenance pathway.

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