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represent new insights about the radio-responsiveness in MMG. They seem promising to clarify the role of miRNAs in DNA-damage response to radiation in microgravity, thus

The studies on molecular mechanisms of bystander effect could have great implications in evaluating radiation risk of IR exposures, and also have the potential to reassess radiation damage models currently used in radiotherapy. The radiation-induced bystander effect was shown to occur in a number of experimental systems both *in vitro* and *in vivo* and it is supposed to be realized through several pathways of transmission of the stress signal: a direct cellular contact, interaction through gap-junctions and through the culture medium of the irradiated cells. In our experimental system the conditioned medium was the main way by which the irradiated cells communicate their stressed condition to the non-irradiated cells. ROS released by irradiated TK6 cells into the culture medium were short-lived and probably other soluble molecules are necessary to maintain high the level of cell mortality in bystander cells. Recent studies, investigating on the nature of such molecules, suggest that fragments of extracellular genomic DNA, probably released from the apoptotic irradiated cells in the culture medium, are able to induce the bystander effects (Ermakov et al., 2011). Such DNA fragments bind to the Toll-like receptors family, leading to a signaling mechanism whose outcome is the dynamic transformation of the cytoskeleton and alteration in the spatial localization of chromatin portions in the nucleus. Thus, in bystander cells, as for microgravity-incubated lymphocytes, modifications in the nuclear structural

We gratefully acknowledge Dr. Cristiano De Pittà and Dr. Chiara Romualdi of the Department of Biology, University of Padova, for miRNA and mRNA expression profiling and statistical assistance. We acknowledge Dr. Vito Barbieri of the Department of Oncological and Surgical Sciences of Padova's University for cell irradiation with –rays and Roberto Cherubini of the INFN, Laboratori Nazionali di Legnaro, Padova, for cell

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**2** 

*Italy* 

**Interactions by Carcinogenic Metal** 

Simona Catalani and Pietro Apostoli

*University of Brescia,* 

*Department of Experimental and Applied Medicine, Section of Occupational Health and Industrial Hygiene,* 

**Compounds with DNA Repair Processes** 

Some metal compounds, including arsenic, beryllium, cadmium, chromium and nickel have long been recognized as human and animal carcinogens, while for other as antimony, cobalt, lead and vanadium their carcinogenic action are probable or possible. Except chromium (VI), carcinogenic metals are only weak mutagens in mammalian cells and often inactive in bacterial assays. Since the mutagenicity in bacterial assays indicates reactivity with DNA, metals are thought to exert genotoxicity mainly by indirect mechanisms. The four main, partly overlapping, DNA repair pathways operating in mammalian cells are base excision, mismatch, nucleotide excision and recombinational repair; each of repair pathways is involved in the removal of the specific DNA lesions. In addition, many carcinogenic metal compounds at low concentrations have been identified as inhibitors of the repair of DNA damage caused by other xenobiotics or endogenous factor. Furthermore, DNA is not only damaged by environmental mutagens including UV-light and polycyclic aromatic hydrocarbons, but also by reactive oxygen species generated from the same metallic elements. Failure to repair DNA damage can result in the accumulation of damaged DNA,

The potential target of metallic elements on DNA repair proteins are the zinc finger structures in their DNA binding motifs. Within these structures, zinc is complexed to four cysteines and/or histidines, folding different structural domains mediating DNA-protein as well as protein-protein interactions. It is estimated that about 1% of all mammalian genes encode zinc finger proteins, which are involved in many processes maintaining genomic integrity (Mackay & Crossley, 1998). The zinc ions do not participate in interactions conveyed by zinc finger domains, but are necessary for their function since they maintain their three-dimensional structures. In the case of transcription factors and DNA repair proteins, the absence of metal ions lead to loss in DNA-binding capacity. The functions of individual zinc finger include recognition of structures and sequences of nucleic acids and proteins. The majority of identified zinc finger may be classified as transcription factors. Another well known function of various zinc finger motifs, is the assembly of multiprotein

**1. Introduction** 

mutation and carcinogenesis.

**2. Mechanism of action** 

