Preface

In previous decades, we have seen a rapid advancement in our fundamental understanding of DNA repair, as well as translational application to medicine in general. In this context, a comprehensive review of key concepts in DNA repair is well beyond the scope of the presented text. Instead, select topics pertinent to the field are selected for presentation, with the goal of highlighting paradigmatic advances.

This book is divided into 26 chapters, and compartmentalized into four parts: DNA Damaging Agents, Mechanistic Insights, Methods in DNA Repair, and Insights into Therapeutic Strategies. Each component discusses key concepts in DNA repair. Selected articles are further meant to demonstrate how scientific ideas are developed, tested, dialogued and matured. It is my sincere hope that the articles presented will stimulate and inspire thoughts that, in turn, contribute to this critically important field.

> **Clark C. Chen, M.D., Ph.D.**  University of California, San Diego USA

**Part 1** 

**DNA Damaging Agents** 

**Part 1** 

**DNA Damaging Agents** 

**1** 

*Italy* 

**The DNA-Damage Response to** 

Cristina Girardi and Lucia Celotti *University of Padova, Department of Biology,* 

**Ionizing Radiation in Human Lymphocytes** 

The human genome is constantly subjected to DNA damage derived from endogenous and exogenous sources. Normal cellular metabolism can give raise to DNA damage through free radicals production and replication errors, whereas environmental agents, such as ultraviolet (UV) and ionizing radiation (IR), induce specific types of lesions. DNA damage can ultimately lead to genomic instability and carcinogenesis if not properly addressed, thus an elaborate network of proteins has evolved in cells to maintain genome integrity through a pathway termed the DNA-damage response (DDR). DDR allows DNA damage detection, signal propagation and transduction to a multitude of effector proteins, which promote cell survival and activate cell cycle arrest to allow DNA repair. When cells are unable to properly repair DNA, apoptosis or senescence pathways may be triggered, thus eliminating the possibility of passing on damaged or unrepaired genetic material to its progeny. The ultimate goal of DDR is to protect the integrity of genetic information and its faithful transmission, either to DNA by replication or to mRNA by transcription. Therefore, dysregulation of DDR pathway can contribute to carcinogenesis and developmental defects. Ionizing radiation represents a mutagen agent to which human population is exposed due to environmental, professional or accidental reasons. The biological effects of IR depend on the quality and the dose of radiation and on the cell type. Linear energy transfer (LET) represents the energy lost per unit distance as an ionizing particle travels through a material, and it is used to quantify the effects of IR on biological specimens. High-LET radiation (i.e. alpha-particles, neutrons, protons) are densely IR since they lose the energy throughout a small distance, causing dense ionization along their track with high localized multiple DNA damage. Low-LET radiation, such as X and -rays, are sparsely IR since they produce ionizations sparsely along their track and, hence, almost homogeneously within a cell. The biological effect of high-LET radiations are in general much higher than those of low-LET radiations with the same energy. This is because high-LET radiation deposits most of its energy within the volume of one cell and the damage to DNA is therefore larger (Anderson et al., 2002; Brenner & Ward, 1992; Prise et al., 2001). Radiation is potentially harmful to humans, because the ionization it produces can significantly alter the structure of molecules within a living cell.The exposure to ionizing radiation elicits a complex cell response to overcome the dangerous effects of DNA-radiation interaction, such as reactive oxygen species (ROS) production, base oxidation and DNA breaks formation (i.e. single-

**1. Introduction** 

Maddalena Mognato, Mauro Grifalconi, Sabrina Canova,
