Complex DNA Damage: A Route to Radiation-Induced Genomic Instability and Carcinogenesis

Abstract

Cellular effects of ionizing radiation (IR) are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs), single strand breaks (SSBs) and base lesions within a short DNA region of up to 15–20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1) repair resistant, increasing genomic instability (GI) and malignant transformation and (2) can be considered as persistent “danger” signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity). Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.

Reduction in replication‐independent endogenous DNA double‐strand breaks promotes genomic instability during chronological aging in yeast

“…Cells contain proteins that produce or maintain epigenetic markers but repair DNA lesions. These lesions promote genomic instability, whereas epigenetic markers help prevent mutations (3,(9)(10)(11). Physiological RIND-EDSBs display many characteristics of epigenetic markers and share no similarities with DNA lesions, whereas pathological DSBs must be immediately repaired to prevent apoptotic signaling (12).…”

RMI1 contributes to DNA repair and to the tolerance to camptothecin

“…HR is a high‐fidelity DNA repair mechanism that functions to rejoin DSBs (37). HR, which occurs in the S or G2 phase of the cell cycle, uses a homologous DNA sequence as a template to guide the faithful repair of DSBs (38). RAD51 is a highly conserved protein that catalyzes DNA repair via HR and is a major DNA repair pathway that directly modulates cellular sensitivity to DNA‐damaging treatments.…”

The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration

“…Fractionated radiation regimens may thwart the effects of radiation-induced tumor cell migration by killing recruited cells through subsequent radiation fractions. Recent studies examining the induction of immune responses following DNA damage have also shown a radiation dose and fractionation dependence [24, 25]. The interplay between all these processes will determine overall tumor response to radiation treatment.…”