Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition

Idowu, Michael A.

doi:10.7750/biodiscovery.2013.9.4

Cited by 4 publications

(9 citation statements)

References 128 publications

(178 reference statements)

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“…Cisplatin treatment alone also resulted in the repression of ATM and ATR transcription (Fig. 8), which opens up the possibility of the existence of threshold levels and activation induced repression mechanisms [38]. Indeed combination of NRF2 SiRNA and cisplatin did not further repress the transcriptional activities of ATM and ATR promoters.…”

Section: Discussionmentioning

confidence: 99%

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NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM-and ATR-dependent DDR and NRF2-mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both ATM and ATR expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance.

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Section: Discussionmentioning

confidence: 99%

“…The fate of cell depends on the pathway activated, which is decided by the extent of DNA damage. [38,39]. Thus DDR is a signal transduction pathway that is coordinated to accord with other cellular activities such as cell cycle progression and programmed death.…”

Section: Introductionmentioning

confidence: 99%

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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“…9 -left image). [6]. The TRM inference method used to derive the transformation matrix ensures that the Jacobian-based model is consistent with the historical data as demonstrated in Fig.…”

Section: Dynamic Modelling Of Biological Systemsmentioning

confidence: 96%

“…Here we introduce a new form of ODE-based discretization theory, apply knowledge of this to develop a new algorithm called TRM [1,2,3,4,5,6], and demonstrate an application of TRM (causal inference) on test networks [2] and a real biological system using quantitative time series data of key kinases of the DDR pathway [6].…”

Section: Introductionmentioning

confidence: 99%

Instantaneous Modelling and Reverse Engineering of Data-Consistent Prime Models in Seconds!

Idowu

2015

Procedia Computer Science

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A theoretical framework that supports automated construction of dynamic prime models purely from experimental time series data has been invented and developed, which can automatically generate (construct) data-driven models of any time series data in seconds. This has resulted in the formulation and formalisation of new reverse engineering and dynamic methods for automated systems modelling of complex systems, including complex biological, financial, control, and artificial neural network systems. The systems/model theory behind the invention has been formalised as a new, effective and robust system identification strategy complementary to process-based modelling. The proposed dynamic modelling and network inference solutions often involve tackling extremely difficult parameter estimation challenges, inferring unknown underlying network structures, and unsupervised formulation and construction of smart and intelligent ODE models of complex systems. In underdetermined conditions, i.e., cases of dealing with how best to instantaneously and rapidly construct data-consistent prime models of unknown (or well-studied) complex system from small-sized time series data, inference of unknown underlying network of interaction is more challenging. This article reports a robust step-by-step mathematical and computational analysis of the entire prime model construction process that determines a model from data in less than a minute.

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“…Induced overexpression of Bmal1 was shown to inhibit tumour growth and increase the sensi vity of human colorectal carcinoma cells to oxalipla n [36]. This process is mediated by cell cycle arrest in G2/M phase presumably mediated by ATM, which has been considered as a cancer target [303,304]. Re noid-related orphan receptors (RORs) have been shown to play roles in the regula on of lipid and steroid metabolism and the pathogenesis of cancer [305][306][307].…”

Section: 2mentioning

confidence: 99%

DNA damage and the circadian clock

Chakarov¹,

Petkova²,

Russev³

et al. 2014

Biodiscovery

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The role of the circadian clock has already been demonstrated for virtually all physiological processes, but it was only recently shown that cells were more sensi ve to DNA damage at specific mes of the day; that the peak of synthesis of mRNA and proteins of genes coding for products involved directly or indirectly in DNA repair was differen ally med in different ssues; and that the growth of some types of cancer followed a circadian pa ern. The paper reviews the specifici es of the clockwork mechanism in living cells associated with repair of DNA damage with regards to its role in ageing and carcinogenesis. The role of heritable polymorhisms and soma c muta ons in the risk for development of common diseases (cancer, but also other types of diseases and condi ons, such as obesity and metabolic syndrome), their course and the possible outcomes is reviewed in animal models and in man. The circadian oscilla ons in the levels of major proteins of DNA-damage related signalling and DNA repair are discussed in rela on to differen al mechanisms of defence against genotoxic damage. The paper outlines the modern concept of 'chronotherapy' -that is, an cancer therapy administered at specific mes of the day/ night cycle that could be associated with be er outcomes in some pa ents and analyses the individual variance in the tolerability of chronotherapy vs. maximum-dose an cancer therapy.Cita on: Chakarov S, Petkova R, Russev GCh, Zhelev N. DNA damage and the circadian clock.

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Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition

Cited by 4 publications

References 128 publications

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Instantaneous Modelling and Reverse Engineering of Data-Consistent Prime Models in Seconds!

DNA damage and the circadian clock

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