K1 – Induction and repair of oxidative clustered DNA damage and its biological importance for humans

Alexandros G. Georgakilas1, Ioanna Tremi1, Spyridon A. Kalospyros1, Maria P. Souli1, 2, Theodora-Dafni Michalettou1, Christine Vasileiou1, Ifigeneia V.Mavragani1, Antonio Pantelias3, Georgia I. Terzoudi3, Zacharenia Nikitaki1
1 DNA damage laboratory, Physics Department, School of Applied Mathematics and Physical Sciencies, National Technical University of Athens, Iroon Polytechneiou 9, Zografou 15780, Greece
2 Atominstitut, Technische Universität Wien, Stadionallee 2, Wien 1020, Austria
3 Laboratory of Health Physics, Radiobiology & Cytogenetics, Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Centre for Scientific Research “Demokritos”, Athens, Greece

Exposure to ionizing radiation (IR) of low–to-high linear energy transfer (LET) inflicts a variety of pernicious effects to biological systems. But which is considered the main instigator of these effects? With increasing LET, like when a charged particle traverses a cell, the induced-DNA damage is dense in space and time and it’s called clustered or complex DNA damage. Both types of cells (malignant and normal) and across species, respond to IR-induced complex DNA damage by activating a multifaceted network of initial DNA damage response signaling cascade, which along with its subsequent damage processing (repair) pathways are called DNA damage response and repair (DDR/R) [1]. Clustered DNA damage hobbles cellular repair machinery leading to cell death or to misrepair DNA, causing in turn, genomic instability [2]. Upon irradiation, the underlying biological processes that determine cellular fate (cell death, senescence or survival with mutations) are practically the complexity of DNA damage and fidelity of repair. In this presentation, we will discuss: the importance of clustered DNA lesions comprised strand breaks and oxidative base damage, available DNA damage prediction tools based on Monte Carlo simulations [3] as well as DNA damage detection strategies along with the state of the art microscopy advantages and the resolution limit [4]. At the same time, a historical perspective on the progress of understanding the repair mechanisms used to confront this severe type of cellular stress and the need for systemic biology approaches needed to tackle the problem better. Last but not least, we will briefly present latest data from our laboratory on the above topics and conclude underscoring the IR-systemic effects triggered by complex DNA damage and implications for cancer treatment using radiation therapy (RT).
Selected references
1. Mavragani, I.V.; Nikitaki, Z.; Kalospyros, S.A.; Georgakilas, A.G. Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance. Cancers 2019, 11, 1789.
2. Pantelias, A.; Karachristou, I.; Georgakilas, A.G.; Terzoudi, G.I. Interphase Cytogenetic Analysis of Micronucleated and Multinucleated Cells Supports the Premature Chromosome Condensation Hypothesis as the Mechanistic Origin of Chromothripsis.  Cancers 2019, 11, 1123.
3. Chatzipapas, K.P.; Papadimitroulas, P.; Emfietzoglou, D.; Kalospyros, S.A.; Hada, M.; Georgakilas, A.G.; Kagadis, G.C. Ionizing Radiation and Complex DNA Damage: Quantifying the Radiobiological Damage Using Monte Carlo Simulations. Cancers 2020, 12, 799.