War without weapons:constitution of healthy and pathological phenotypes associated with polymorphisms in genes involved in the maintenance of genome integrity

Capacity to repair DNA damage may vary significantly between individuals coming out as healthy on routine physical and laboratory examinations. This variance does not generally cause distress or disease unless in case that specific triggers are present, but, taken together with other factors, may increase the risk for certain types of cancer or may modulate the outcome of anticancer therapies. Carriership of certain polymorphic variants in DNA repair genes may also modify the course of the normal process of aging. The present paper reviews the role of some of the common polymorphisms in DNA repair genes and in genes involved in the maintenance of genomic integrity; and their association, separately or in combination, with the ‘healthy’ phenotype and with certain diseases and conditions related to exposure to increased levels of oxidative damage

Repair, abort, ignore? Strategies for dealing with UV damage

DNA repair is a prominent member of the nuclear transactions triad (replication, transcription, and repair). Sophisticated mechanisms govern the cellular process of decision-making (to repair or not to repair, to proceed with cell cycle or not and, eventually, to let the cell survive or die) and the temporal and spatial distribution of the DNA repair activities. UV radiation is a very common and virtually unavoidable mutagen whose carcinogenic potential seems to accumulate over time. Various strategies have been developed to avoid or decrease UV damage to cellular DNA, based on prevention of exposure as well as on post-irradiation measures. It is, however, important to acknowledge that the individual capacity for DNA repair varies during the life of the individual and must, therefore, be assessed so as to determine whether the individual is coping with environmental UV damage. Assessment of individual repair capacity might greatly modify the existing therapeutic strategies for common cancers and ought to become a routine part of health prophylaxis

Differential genetic advantages in youth and in aging, or how to die healthy

Human society ages at a steady rate, that is, the proportion of adult and elderly individuals increases constantly because of improved living conditions and the advances in medical care. This means that very soon the tradeoff between the advantages in old age conferred by alleles disadvantageous or neutral in young age would begin to show, providing the fascinating opportunity of studying the interplay between genetic factors and environment outside the framework of reproductive capacity and in the unique milieu of the aging cell. Being healthy and/or health-conscious in youth does not guarantee for successful aging or even that the person would live up to the average life expectancy of the population. Therefore, successful aging and longevity are related to a healthy-conscious attitude to a degree only. The present paper reviews the basic genetic and evolutionary mechanisms which have operated during human history so as to ensure survival of humankind and the possible factors preventing or contributing to successful aging

ATM in focus:a damage sensor and cancer target

The ability of a cell to conserve and maintain its native DNA sequence is fundamental for the survival and normal functioning of the whole organism and protection from cancer development. Here we review recently obtained results and current topics concerning the role of the ataxia-telangiectasia mutated (ATM) protein kinase as a damage sensor and its potential as therapeutic target for treating cancer. This monograph discusses DNA repair mechanisms activated after DNA double-strand breaks (DSBs), i.e. non-homologous end joining, homologous recombination and single strand annealing and the role of ATM in the above types of repair. In addition to DNA repair, ATM participates in a diverse set of physiological processes involving metabolic regulation, oxidative stress, transcriptional modulation, protein degradation and cell proliferation. Full understanding of the complexity of ATM functions and the design of therapeutics that modulate its activity to combat diseases such as cancer necessitates parallel theoretical and experimental efforts. This could be best addressed by employing a systems biology approach, involving mathematical modelling of cell signalling pathways

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

The DNA Damage Response (DDR) pathway represents a signalling mechanism that is activated in eukaryotic cells following DNA damage and comprises of proteins involved in DNA damage detection, DNA repair, cell cycle arrest and apoptosis. This pathway consists of an intricate network of signalling interactions driving the cellular ability to recognise DNA damage and recruit specialised proteins to take decisions between DNA repair or apoptosis. ATM and ATR are central components of the DDR pathway. The activities of these kinases are vital in DNA damage induced phosphorylational induction of DDR substrates. Here, firstly we have experimentally determined DDR signalling network surrounding the ATM/ATR pathway induced following double stranded DNA damage by monitoring and quantifying time dependent inductions of their phosphorylated forms and their key substrates. We next involved an automated inference of unsupervised predictive models of time series data to generate in silico (molecular) interaction maps. We characterized the complex signalling network through system analysis and gradual utilisation of small time series measurements of key substrates through a novel network inference algorithm. Furthermore, we demonstrate an application of an assumption-free reverse engineering of the intricate signalling network of the activated ATM/ATR pathway. We next studied the consequences of such drug induced inductions as well as of time dependent ATM kinase inhibition on cell survival through further biological experiments. Intermediate and temporal modelling outcomes revealed the distinct signaling profile associated with ATM kinase activity and inhibition and explained the underlying signalling mechanism for dual ATM functionality in cytotoxic and cytoprotective pathways

Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance

Seliciclib (R-Roscovitine) was identified as an inhibitor of CDKs and has undergone drug development and clinical testing as an anticancer agent. In this review, the authors describe the discovery of Seliciclib and give a brief summary of the biology of the CDKs Seliciclib inhibits. An overview of the published in vitro and in vivo work supporting the development as an anti-cancer agent, from in vitro experiments to animal model studies ending with a summary of the clinical trial results and trials underway is presented. In addition some potential non-oncology applications are explored and the potential mode of action of Seliciclib in these areas is described. Finally the authors argue that optimisation of the therapeutic effects of kinase inhibitors such as Seliciclib could be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division

Targeting ATM pathway for therapeutic intervention in cancer

The Ataxia Telangiectasia Mutated gene encodes the ATM protein, a key element in the DNA damage response (DDR) signalling pathway responsible for maintaining genomic integrity within the cell. The ATM protein belongs to a family of large protein kinases containing the phosphatidylinositol-3 catalytic domain, including ATM, ATR and PI3K. ATM provides the crucial link between DNA damage, cell cycle progression and cell death by first sensing double stranded DNA breaks and subsequently phosphorylating and activating other downstream proteins functioning in DNA damage repair, cell cycle arrest and apoptotic pathways,. Mammalian cells are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain DNA integrity or activate alternative cell fate pathways. This review covers the role of ATM in DDR signalling and describes the interaction of the ATM kinase with other proteins in order to fulfil its various functions. Special emphasis is given to how the growing knowledge of the DDR can help identify drug targets for cancer therapy, thus providing a rationale for exploiting the ATM pathway in anticancer drug development. Moreover, we discuss how a network modelling approach can be used to identify and characterise ATM inhibitors and predict their therapeutic potential

Understanding tissue morphology: model repurposing using the CoSMoS process

We present CoSMoS as a way of structuring thinking on how to reuse parts of an existing model and simulation in a new model and its implementation. CoSMoS provides a lens through which to consider, post-implementation, the assumptions made during the design and implementation of a software simulation of physical interactions in the formation of vascular structures from endothelial cells. We show how the abstract physical model and its software implementation can be adapted for a different problem: the growth of cancer cells under varying environmental perturbations. We identify the changes that must be made to adapt the model to its new context, along with the gaps in our knowledge of the domain that must be filled by wet-lab experimentation when recalibrating the model. Through parameter exploration, we identify the parameters that are critical to the dynamic physical structure of the modelled tissue, and we calibrate these parameters using a series of in vitro experiments. Drawing inspiration from the CoSMoS project structure, we maintain confidence in the repurposed model, and achieve a satisfactory degree of model reuse within our in silico experimental system

Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells

Cells are constantly exposed to Reactive Oxygen Species (ROS) produced both endogenously to meet physiological requirements and from exogenous sources. While endogenous ROS are considered as important signalling molecules, high uncontrollable ROS are detrimental. It is unclear how cells can achieve a balance between maintaining physiological redox homeostasis and robustly activate the antioxidant system to remove exogenous ROS. We have utilised a Systems Biology approach to understand how this robust adaptive system fulfils homeostatic requirements of maintaining steady-state ROS and growth rate, while undergoing rapid readjustment under challenged conditions. Using a panel of human ovarian and normal cell lines, we experimentally quantified and established interrelationships between key elements of ROS homeostasis. The basal levels of NRF2 and KEAP1 were cell line specific and maintained in tight correlation with their growth rates and ROS. Furthermore, perturbation of this balance triggered cell specific kinetics of NRF2 nuclear–cytoplasmic relocalisation and sequestration of exogenous ROS. Our experimental data were employed to parameterise a mathematical model of the NRF2 pathway that elucidated key response mechanisms of redox regulation and showed that the dynamics of NRF2-H2O2 regulation defines a relationship between half-life, total and nuclear NRF2 level and endogenous H2O2 that is cell line specific