In Silico Investigation of the Biological Implications of Complex DNA Damage with Emphasis in Cancer Radiotherapy through a Systems Biology Approach.

Athanasia Pavlopoulou,Işıl Takan,Ifigeneia V Mavragani,Alexandros G Georgakilas,Lynn Harrison,Evangelos Gioukakis,Seyedehsadaf Asfa,Zacharenia Nikitaki,Jean-Pierre Pouget

doi:10.3390/molecules26247602

Abstract

Different types of DNA lesions forming in close vicinity, create clusters of damaged sites termed as “clustered/complex DNA damage” and they are considered to be a major challenge for DNA repair mechanisms resulting in significant repair delays and induction of genomic instability. Upon detection of DNA damage, the corresponding DNA damage response and repair (DDR/R) mechanisms are activated. The inability of cells to process clustered DNA lesions efficiently has a great impact on the normal function and survival of cells. If complex lesions are left unrepaired or misrepaired, they can lead to mutations and if persistent, they may lead to apoptotic cell death. In this in silico study, and through rigorous data mining, we have identified human genes that are activated upon complex DNA damage induction like in the case of ionizing radiation (IR) and beyond the standard DNA repair pathways, and are also involved in cancer pathways, by employing stringent bioinformatics and systems biology methodologies. Given that IR can cause repair resistant lesions within a short DNA segment (a few nm), thereby augmenting the hazardous and toxic effects of radiation, we also investigated the possible implication of the most biologically important of those genes in comorbid non-neoplastic diseases through network integration, as well as their potential for predicting survival in cancer patients.

Highlights

Many decades of research in radiobiology have shown that the inability of cells to repair DNA damage can be markedly detrimental, for the cells but for the whole organism, as well [1,2]
The aim of this study was to find human genes that are explicitly activated upon induction of clustered/complex DNA damage, beyond the expected standard DNA repair mechanisms
The gene IRF3 is implicated in the cGASSTING signalling pathway which is related to cellular response to cytosolic dsDNA [31]; in this case free cytosolic dsDNAs acts as endogenous danger signaling molecules or disease-associated molecular patterns (DAMP) [32] which can initiate downstream proinflammatory signaling events [33]

Summary

Introduction

Many decades of research in radiobiology have shown that the inability of cells to repair DNA damage can be markedly detrimental, for the cells but for the whole organism, as well [1,2]. Complex DNA lesions are commonly caused by ionizing radiation (IR), as low energy photons or charged particles traversing cells induce clusters of excitations and ionizations, causing lesions within a short DNA segment (a few nm), augmenting the hazardous effects of radiation [6]. Such damage clusters are repair resistant, increasing genomic instability and malignant transformation, and can be considered as “danger” signals promoting chronic inflammatory response and leading to detrimental effects to the organism, such as radiation toxicity [7]. Our central hypothesis is that complex DNA damage induced by IR is the primary instigator of biological and clinical responses to cancer radiotherapy (RT)

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Conclusion