Status report of a systematic investigation on low-dose ionizing radiation effects in mammalian cells

In the last 15 years a growing interest in the biological effects induced by low doses of ionizing radiation has arisen in the scientific community, due to an increasing number of experimental evidences showing a plethora of non-linear effects occurring after low-dose irradiations. In particular, hyper-radiosensitivity and induced radioresistance (HRS/IRR) have been reported after exposure to low- and high-LET radiation, in human (normal and tumoural) and other mammalian cells in vitro. In this framework, Chinese hamster V79 cells, human primary fibroblasts (HFFF2) and murine embryonic fibroblasts (MEFs) were irradiated with broadbeams of protons in the dose range 0.1–5.0Gy and at 1 Gy/min dose-rate. Cellular response has been evaluated in terms of cell survival, micronuclei induction, chromosomal aberrations and telomere length alterations. For comparison purpose, the same end-points were studied after X/γ-rays irradiation

Identification of BC005512 as a DNA Damage Responsive Murine Endogenous Retrovirus of GLN Family Involved in Cell Growth Regulation

Genotoxicity assessment is of great significance in drug safety evaluation, and microarray is a useful tool widely used to identify genotoxic stress responsive genes. In the present work, by using oligonucleotide microarray in an in vivo model, we identified an unknown gene BC005512 (abbreviated as BC, official full name: cDNA sequence BC005512), whose expression in mouse liver was specifically induced by seven well-known genotoxins (GTXs), but not by non-genotoxins (NGTXs). Bioinformatics revealed that BC was a member of the GLN family of murine endogenous retrovirus (ERV). However, the relationship to genotoxicity and the cellular function of GLN are largely unknown. Using NIH/3T3 cells as an in vitro model system and quantitative real-time PCR, BC expression was specifically induced by another seven GTXs, covering diverse genotoxicity mechanisms. Additionally, dose-response and linear regression analysis showed that expression level of BC in NIH/3T3 cells strongly correlated with DNA damage, measured using the alkaline comet assay,. While in p53 deficient L5178Y cells, GTXs could not induce BC expression. Further functional studies using RNA interference revealed that down-regulation of BC expression induced G1/S phase arrest, inhibited cell proliferation and thus suppressed cell growth in NIH/3T3 cells. Together, our results provide the first evidence that BC005512, a member from GLN family of murine ERV, was responsive to DNA damage and involved in cell growth regulation. These findings could be of great value in genotoxicity predictions and contribute to a deeper understanding of GLN biological functions

The multiple facets of atrx protein

ATRX gene codifies for a protein member of the SWI-SNF family and was cloned for the first time over 25 years ago as the gene responsible for a rare developmental disorder characterized by α-thalassemia and intellectual disability called ATRX syndrome (Alpha Thalassemia/mental Retardation syndrome X-linked). Since its discovery as a helicase involved in alpha-globin gene transcriptional regulation, our understanding of the multiple roles played by the ATRX protein increased continuously, leading to the recognition of this multifaceted protein as a central “caretaker” of the human genome involved in cancer suppression. In this review, we report recent advances in the comprehension of the ATRX manifold functions that encompasses heterochromatin epigenetic regulation and maintenance, telomere function, replicative stress response, genome stability, and the suppression of endogenous transposable elements and exogenous viral genomes