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Biamonti G.,CNR Institute of Molecular Genetics
Cold Spring Harbor perspectives in biology | Year: 2010

Nuclear stress bodies (nSBs) are unique subnuclear organelles which form in response to heat shock. They are initiated through a direct interaction between heat shock transcription factor 1 (HSF1) and pericentric tandem repeats of satellite III sequences and correspond to active transcription sites for noncoding satellite III transcripts. Given their unusual features, nSBs are distinct from other known transcription sites. In stressed cells, they are thought to participate in rapid, transient, and global reprogramming of gene expression through different types of mechanisms including chromatin remodeling and trapping of transcription and splicing factors. The analysis of these atypical and intriguing structures uncovers new facets of the relationship between nuclear organization and nuclear function. Source

Aghemo A.,Am gliavacca Center For The Study Of Liver Disease | De Francesco R.,CNR Institute of Molecular Genetics
Hepatology | Year: 2013

Most direct-acting antivirals (DAAs) that are being developed as therapy against hepatitis C virus target the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers different target sites: the catalytic domain for nucleos(t)ide analogues as well as a number of allosteric sites for nonnucleos(t)ide inhibitors. Two NS3/4A protease inhibitors have been approved recently, and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development. These agents can achieve very high cure rates when combined with pegylated interferon-β and ribavirin and show promising clinical results when administered in all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small-molecule drug development are emerging, such as p7 or NS4B and viral entry. Future research will need to define well-tolerated and cost-effective DAA combinations that provide the highest rates of viral eradication in all patients (including those with advanced liver disease), the broadest spectrum of action on viral genotypes showing minimal or no clinical resistance, and the shortest treatment duration. © 2013 American Association for the Study of Liver Diseases. Source

D'Adda di Fagagna F.,Institute of Molecular Oncology Foundation | D'Adda di Fagagna F.,CNR Institute of Molecular Genetics
Trends in Cell Biology | Year: 2014

Historically, the role of cellular RNA has been subordinate and ancillary to DNA. Protein-coding mRNA conveys the information content of DNA, and transfer RNAs and ribosomal RNAs allow the polymerization of amino acids into proteins. The discovery of non-protein-coding RNAs (ncRNAs) provided an additional role for RNA in finely tuning DNA expression. However, it has recently become apparent that the safeguard of DNA integrity depends on small ncRNAs acting at the site of DNA lesions to signal the presence of DNA damage in the cell, and on the genes involved in their biogenesis to achieve accurate DNA repair. I review here evidence supporting a role for small ncRNAs, termed DNA damage-response RNAs (DDRNAs) or double-strand break (DSB)-induced RNAs (diRNAs), that are generated at sites of DNA damage and control the DNA damage response (DDR). I also discuss their biogenesis, potential mechanisms of action, and their relevance in cancer. © 2013 Elsevier Ltd. Source

Bodega B.,CNR Institute of Molecular Genetics | Orlando V.,King Abdullah University of Science and Technology
Current Opinion in Cell Biology | Year: 2014

The days of 'junk DNA' seem to be over. The rapid progress of genomics technologies has been unveiling unexpected mechanisms by which repetitive DNA and in particular transposable elements (TEs) have evolved, becoming key issues in understanding genome structure and function. Indeed, rather than 'parasites', recent findings strongly suggest that TEs may have a positive function by contributing to tissue specific transcriptional programs, in particular as enhancer-like elements and/or modules for regulation of higher order chromatin structure. Further, it appears that during development and aging genomes experience several waves of TEs activation, and this contributes to individual genome shaping during lifetime. Interestingly, TEs activity is major target of epigenomic regulation. These findings are shedding new light on the genome-phenotype relationship and set the premises to help to explain complex disease manifestation, as consequence of TEs activity deregulation. © 2014. Source

Galietta L.J.V.,CNR Institute of Molecular Genetics
Pediatric Drugs | Year: 2013

Cystic fibrosis (CF), a severe genetic disease, is caused by mutations that alter the structure and function of CFTR, a plasma membrane channel permeable to chloride and bicarbonate. Defective anion transport in CF irreversibly damages the lungs, pancreas, liver, and other organs. CF mutations cause loss of CFTR function in multiple ways. In particular, class 3 mutations such as p.Gly551Asp strongly decrease the time spent by CFTR in the open state (gating defect). Instead, class 2 mutations impair the maturation of CFTR protein and its transport from the endoplasmic reticulum to the plasma membrane (trafficking defect). The deletion of phenylalanine 508 (p.Phe508del), the most frequent mutation among CF patients (70-90 %), destabilizes the CFTR protein, thus causing both a trafficking and a gating defect. These two defects can be overcome with drug-like molecules generically called correctors and potentiators, respectively. The potentiator Kalydeco™ (also known as Ivacaftor or VX-770), developed by Vertex Pharmaceuticals, has been recently approved by the US FDA and the European Medicines Agency (EMA) for the treatment of CF patients carrying at least one CFTR allele with the p.Gly551Asp mutation (2-5 % of all patients). In contrast, the corrector VX-809, which significantly improves p.Phe508del-CFTR trafficking in vitro, is still under study in clinical trials. Because of multiple defects caused by the p.Phe508del mutation, it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action. This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect. © 2013 Springer International Publishing Switzerland. Source

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