DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial Drugs

Pommier, ﻿Yves; Leo, Elisabetta; Zhang, Hongliang; Marchand, Christophe

doi:10.1016/j.chembiol.2010.04.012

Cited by 1,599 publications

(1,556 citation statements)

References 104 publications

(138 reference statements)

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“…Both these stabilize the covalent ternary complexes of the topoisomerases with DNA. DSBs can be formed when these complexes are encountered by the replication forks [Pommier et al, 2010].…”

Section: Degradation Of P12 and The Conversion Of Pol D4 To Pol D3 Inmentioning

confidence: 99%

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Lee

Zhang

Lin

et al. 2012

Environ and Mol Mutagen

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The p12 subunit of polymerase delta (Pol d) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol d4 holoenzyme to the heterotrimer, Pol d3. We review studies that establish that Pol d3 formation is an event that could have a major impact on cellular processes in genomic surveillance, DNA replication, and DNA repair. p12 degradation is dependent on the apical ataxia telangiectasia and Rad3 related (ATR) kinase and is mediated by the ubiquitin-proteasome system. Pol d3 exhibits properties of an ''antimutator'' polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol d carries out bypass synthesis past small base lesions that engage in spurious base pairing. Chromatin immunoprecipitation analysis and examination of the spatiotemporal recruitment of Pol d to sites of DNA damage show that Pol d3 is the primary form of Pol d associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol d engaged in DNA repair. We propose a model for the switching of Pol d with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol d3. Because of the critical role of Pol d activity in DNA replication and repair, the formation of Pol d3 in response to DNA damage opens the prospect that pleiotropic effects may ensue. This opens the horizons for future exploration of how this novel response to DNA damage contributes to genomic stability. Environ. Mol. Mutagen. 53:683-698, 2012. V V C 2012 Wiley Periodicals, Inc.

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“…Both these stabilize the covalent ternary complexes of the topoisomerases with DNA. DSBs can be formed when these complexes are encountered by the replication forks [Pommier et al, 2010].…”

Section: Degradation Of P12 and The Conversion Of Pol D4 To Pol D3 Inmentioning

confidence: 99%

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Lee

Zhang

Lin

et al. 2012

Environ and Mol Mutagen

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“…18 Etoposide (Eto) is an anticancer drug that functions as a topoisomerase inhibitor. 19 Eto causes errors in DNA synthesis and promotes apoptosis in cancer cells. 20 Remarkably, when we treated cells with Eto, we found that NLK-deficient HCT116 cells showed increased resistance to DNA damage when compared with wild-type HCT116 cells (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage

et al. 2014

Cell Death Differ

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The DNA damage response (DDR) acts as a protective mechanism for maintaining cell homeostasis. Nemo-like kinase (NLK) is a serine/threonine-protein kinase that has an important role in many pathways; however, its function in the DDR has not yet been defined. In our study, NLK-deficient HCT116 cells were found to be resistant to etoposide-induced cell death. We demonstrated that NLK is required for p53 activation in response to DNA damage. Remarkably, mechanistic studies revealed that NLK interacts with p53 and stabilizes p53 by blocking MDM2-mediated p53 ubiquitination and degradation. Furthermore, NLK enhances p53 activity and affects expression downstream of p53. Interestingly, these functions of NLK are not related to its kinase activity. Consistent with these results, NLK-deficient cells have a resistance effect on DNA damage. Therefore, these findings emphasize that NLK is a novel factor in DDR mechanisms.

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“…These layers are capable of extracting features from previous layers with ease. Stacking many of these layers together, we can form a convolutional neural network to automatically extract features from input single‐cell image and then perform classification 16, 17, 18…”

Section: Introductionmentioning

confidence: 99%

DeepScreen: An Accurate, Rapid, and Anti‐Interference Screening Approach for Nanoformulated Medication by Deep Learning

et al. 2018

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Accuracy of current efficacy judgment methods for nanoformulated drug remains unstable due to the interference of nanocarriers. Herein, DeepScreen, a drug screening system utilizing convolutional neural network based on flow cytomerty single‐cell images, is introduced. Compared to existing experimental approaches, the high‐throughput system has superior precision, rapidity, and anti‐interference, and is cost‐cutting with high accuracy. First, it can resist most disturbances from manual factors of complicated evaluation progress. In addition, class activation maps generated from DeepScreen indicate that it may identify and locate the tiny variation from cell apoptosis and slight changes of cellular period caused by drug or even nanoformulated drug action at very early stages. More importantly, the excellent performance of assessment on two types of nanoformulations and fluorescent drug proves the fine generality and anti‐interference of this novel system. All these privileged performances make DeepScreen a very smart and promising system for drug detection.

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DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial Drugs

Cited by 1,599 publications

References 104 publications

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage

DeepScreen: An Accurate, Rapid, and Anti‐Interference Screening Approach for Nanoformulated Medication by Deep Learning

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