@article{%a1.%Yb_89,

title = {Alternative Splicing Changes Promoted by NOVA2 Upregulation in Endothelial Cells and Relevance for Gastric Cancer},

author = {{Di Matteo A} and Belloni E and Pradella D and Chiaravalli AM and Pini GM and Bugatti M and Alfieri R and Barzan C and Franganillo Tena E and Bione S and Terenzani E and Sessa F and Wyatt CDR and Vermi W and Ghigna C},

url = {https://pubmed.ncbi.nlm.nih.gov/37175811/},

doi = {10.3390/ijms24098102},

year  = {2023},

date = {2023-07-27},

urldate = {2023-07-27},

journal = {International journal of molecular sciences},

volume = {24},

issue = {9},

pages = {8102},

abstract = {Angiogenesis is crucial for cancer progression. While several anti-angiogenic drugs are in use for cancer treatment, their clinical benefits are unsatisfactory. Thus, a deeper understanding of the mechanisms sustaining cancer vessel growth is fundamental to identify novel biomarkers and therapeutic targets. Alternative splicing (AS) is an essential modifier of human proteome diversity. Nevertheless, AS contribution to tumor vasculature development is poorly known. The Neuro-Oncological Ventral Antigen 2 (NOVA2) is a critical AS regulator of angiogenesis and vascular development. NOVA2 is upregulated in tumor endothelial cells (ECs) of different cancers, thus representing a potential driver of tumor blood vessel aberrancies. Here, we identified novel AS transcripts generated upon NOVA2 upregulation in ECs, suggesting a pervasive role of NOVA2 in vascular biology. In addition, we report that NOVA2 is also upregulated in ECs of gastric cancer (GC), and its expression correlates with poor overall survival of GC patients. Finally, we found that the AS of the Rap Guanine Nucleotide Exchange Factor 6 (RapGEF6), a newly identified NOVA2 target, is altered in GC patients and associated with NOVA2 expression, tumor angiogenesis, and poor patient outcome. Our findings provide a better understanding of GC biology and suggest that AS might be exploited to identify novel biomarkers and therapeutics for anti-angiogenic GC treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_99,

title = {Identification of bi-allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3},

author = {Lecca M and Bedeschi MF and Izzi C and Dordoni C and Rinaldi B and Peluso F and Caraffi SG and Prefumo F and Signorelli M and Zanzucchi M and Bione S and Ghigna C and Sassi S and Novelli A and Valente EM and Superti-Furga A and Garavelli L and Errichiello E },

url = {https://onlinelibrary.wiley.com/doi/10.1111/cge.14336},

doi = {10.1111/cge.14336},

year  = {2023},

date = {2023-08-08},

journal = {Clinical genetics},

volume = {104},

issue = {2},

pages = {230},

abstract = {Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi-allelic variants in one of the genes involved in the Notch signaling pathway that tunes the ""segmentation clock"" of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio-based exome sequencing (trio-ES) to carry homozygous (c.822-5C>T) or compound heterozygous (c.[863dup];[1063G>A]) and (c.[521G>T];[890T>G]) variants in LFNG. Notably, the c.822-5C>T change, affecting the polypyrimidine tract of intron 5, is the first non-coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio-ES approach in prenatal and neonatal settings.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_37,

title = {DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective},

author = {Secchi M and Lodola C and Garbelli A and Bione S and Maga G},

url = {https://www.mdpi.com/2072-6694/14/15/3820},

doi = {10.3390/cancers14153820},

year  = {2022},

date = {2022-08-18},

journal = {Cancers (Basel)},

volume = {14},

issue = {15},

pages = {3820},

abstract = {RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_131,

title = {A Role for Human DNA Polymerase lambda in Alternative Lengthening of Telomeres},

author = {Mentegari E and Bertoletti F and Kissova M and Zucca E and Galli S and Tagliavini G and Garbelli A and Maffia A and Bione S and Ferrari E and {d'Adda di Fagagna F} and Francia S and Sabbioneda S and Chen LY and Lingner J and Bergoglio V and Hoffmann JS and Hubscher U and Crespan E and Maga G},

url = {https://www.mdpi.com/1422-0067/22/5/2365},

doi = {10.3390/ijms22052365},

year  = {2021},

date = {2021-03-09},

journal = {International journal of molecular sciences},

volume = {22},

number = {5},

pages = {2365},

abstract = {Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol lambda) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol lambda, strongly affects the survival of ALT cells. In vitro, Pol lambda can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol lambda. Pol lambda associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol lambda in the maintenance of telomeres by the ALT mechanism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y,

title = {Protein instability associated with AARS1 and MARS1 mutations causes Trichothiodystrophy},

author = {Botta E and Theil AF and Raams A and Caligiuri G and Giachetti S and Bione S and Accadia M and Lombardi A and Smith DEC and Mendes MI and Swagemakers SMA and van der Spek PJ and Salomons GS and Hoeijmakers JHJ and Yesodharan D and Nampoothiri S and Ogi T and Lehmann AR and Orioli D and Vermeulen W},

url = {https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddab123/6256034},

doi = {10.1093/hmg/ddab123},

year  = {2021},

date = {2021-05-14},

urldate = {2021-05-14},

journal = {Human molecular genetics},

volume = {30},

number = {1711},

issue = {18},

pages = {1720},

abstract = {Trichothiodystrophy (TTD) is a rare hereditary neurodevelopmental disorder defined by sulphur-deficient brittle hair and nails and scaly skin, but with otherwise remarkably variable clinical features. The photosensitive TTD (PS-TTD) form exhibits, in addition, progressive neuropathy and other features of segmental accelerated aging and is associated with impaired genome maintenance and transcription. New factors involved in various steps of gene expression have been identified for the different non-photosensitive forms of TTD (NPS-TTD), which do not appear to show features of premature aging. Here we identify AARS1 and MARS1 variants as new gene defects that cause NPS-TTD. These variants result in instability of the respective gene products alanyl- and methionyl-tRNA synthetase. These findings extend our previous observations that TTD mutations affect the stability of the corresponding proteins and emphasise this phenomenon as a common feature of TTD. Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, the first step in protein translation. The extension of reduced abundance of TTD factors to translation as well as transcription, redefines TTD as a syndrome in which proteins involved in gene expression are unstable.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Ybv,

title = {Reduced levels of prostaglandin I 2 synthase: a distinctive feature of the cancer-free trichothiodystrophy},

author = {Lombardi A and Arseni L and Carriero R and Compe E and Botta E and Ferri D and Uggè M and Biamonti G and Peverali FA and Bione S and Orioli D},

url = {https://www.pnas.org/content/118/26/e2024502118.long},

doi = {10.1073/pnas.2024502118},

year  = {2021},

date = {2021-08-25},

journal = {Proceedings of the National Academy of Sciences of the United States of America.},

volume = {118},

number = {26},

abstract = {The cancer-free photosensitive trichothiodystrophy (PS-TTD) and the cancer-prone xeroderma pigmentosum (XP) are rare monogenic disorders that can arise from mutations in the same genes, namely ERCC2/XPD or ERCC3/XPB Both XPD and XPB proteins belong to the 10-subunit complex transcription factor IIH (TFIIH) that plays a key role in transcription and nucleotide excision repair, the DNA repair pathway devoted to the removal of ultraviolet-induced DNA lesions. Compelling evidence suggests that mutations affecting the DNA repair activity of TFIIH are responsible for the pathological features of XP, whereas those also impairing transcription give rise to TTD. By adopting a relatives-based whole transcriptome sequencing approach followed by specific gene expression profiling in primary fibroblasts from a large cohort of TTD or XP cases with mutations in ERCC2/XPD gene, we identify the expression alterations specific for TTD primary dermal fibroblasts. While most of these transcription deregulations do not impact on the protein level, very low amounts of prostaglandin I2 synthase (PTGIS) are found in TTD cells. PTGIS catalyzes the last step of prostaglandin I2 synthesis, a potent vasodilator and inhibitor of platelet aggregation. Its reduction characterizes all TTD cases so far investigated, both the PS-TTD with mutations in TFIIH coding genes as well as the nonphotosensitive (NPS)-TTD. A severe impairment of TFIIH and RNA polymerase II recruitment on the PTGIS promoter is found in TTD but not in XP cells. Thus, PTGIS represents a biomarker that combines all PS- and NPS-TTD cases and distinguishes them from XP.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Ybv,

title = {TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells. },

author = {Silva B and Arora R and Bione S and Azzalin CM},

url = {https://www.nature.com/articles/s41467-021-24097-6},

doi = {10.1038/s41467-021-24097-6},

year  = {2021},

date = {2021-08-25},

journal = {Nature communications},

volume = {12},

number = {1},

pages = {3760},

abstract = {Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required to initiate ALT, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby triggering BIR and promoting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__420,

title = {GC-AG Introns Features in Long Non-coding and Protein-Coding Genes Suggest Their Role in Gene Expression Regulation},

author = {Abou Alezz M and Celli L and Belotti G and Lisa A and Bione S},

url = {https://www.frontiersin.org/articles/10.3389/fgene.2020.00488/full},

doi = {10.3389/fgene.2020.00488},

year  = {2020},

date = {2020-01-01},

journal = {Frontiers in Genetics - RNA},

volume = {11},

pages = {488-502},

abstract = {Long non-coding RNAs (lncRNAs) are recognized as an important class of regulatory molecules involved in a variety of biological functions. However, the regulatory mechanisms of long non-coding genes expression are still poorly understood. The characterization of the genomic features of lncRNAs is crucial to get insight into their function. In this study, we exploited recent annotations by GENCODE to characterize the genomic and splicing features of long non-coding genes in comparison with protein-coding ones, both in human and mouse. Our analysis highlighted differences between the two classes of genes in terms of their gene architecture. Significant differences in the splice sites usage were observed between long non-coding and protein-coding genes (PCG). While the frequency of non-canonical GC-AG splice junctions represents about 0.8% of total splice sites in PCGs, we identified a significant enrichment of the GC-AG splice sites in long non-coding genes, both in human (3.0%) and mouse (1.9%). In addition, we found a positional bias of GC-AG splice sites being enriched in the first intron in both classes of genes. Moreover, a significant shorter length and weaker donor and acceptor sites were found comparing GC-AG introns to GT-AG introns. Genes containing at least one GC-AG intron were found conserved in many species, more prone to alternative splicing and a functional analysis pointed toward their enrichment in specific biological processes such as DNA repair. Our study shows for the first time that GC-AG introns are mainly associated with lncRNAs and are preferentially located in the first intron. Additionally, we discovered their regulatory potential indicating the existence of a new mechanism of non-coding and PCGs expression regulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%_49,

title = {Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype.},

author = {Theil AF and Botta E and Raams A and Smith DEC and Mendes MI and Caligiuri G and Giachetti S and Bione S and Carriero R and Liberi G and Zardoni L and Swagemakers SMA and Salomons GS and Sarasin A and Lehmann A and van der Spek PJ and Ogi T and Hoeijmakers JHJ and Vermeulen W and Orioli D},

url = {https://www.sciencedirect.com/science/article/abs/pii/S0002929719302423?via%3Dihub},

doi = {10.1016/j.ajhg.2019.06.017},

year  = {2019},

date = {2019-02-13},

journal = {American Journal of Human Genetics},

volume = {105},

number = {2},

pages = {434-440},

abstract = {Brittle and "tiger-tail" hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differentiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaired nucleotide excision repair and basal transcription. Different genes have been found to be associated with non-photosensitive TTD (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIEβ), and RNF113A. However, a relatively large group of these individuals with NPS-TTD have remained genetically uncharacterized. Here we present the identification of an NPS-TTD-associated gene, threonyl-tRNA synthetase (TARS), found by next-generation sequencing of a group of uncharacterized individuals with NPS-TTD. One individual has compound heterozygous TARS variants, c.826A>G (p.Lys276Glu) and c.1912C>T (p.Arg638∗), whereas a second individual is homozygous for the TARS variant: c.680T>C (p.Leu227Pro). We showed that these variants have a profound effect on TARS protein stability and enzymatic function. Our results expand the spectrum of genes involved in TTD to include genes implicated in amino acid charging of tRNA, which is required for the last step in gene expression, namely protein translation. We previously proposed that some of the TTD-specific features derive from subtle transcription defects as a consequence of unstable transcription factors. We now extend the definition of TTD from a transcription syndrome to a "gene-expression" syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%d,

title = {Identification of a novel antiviral micro-RNA targeting the NS1 protein of the H1N1 pandemic human influenza virus and a corresponding viral escape mutation.},

author = {Bavagnoli L and Campanini G and Forte M and Ceccotti G and Percivalle E and Bione S and Lisa A and Baldanti F and Maga G},

url = {https://www.sciencedirect.com/science/article/pii/S0166354219301640?via%3Dihub},

doi = {10.1016/j.antiviral.2019.104593},

year  = {2019},

date = {2019-11-30},

journal = {Antiviral research},

volume = {171},

pages = {104593},

abstract = {The influenza A virus (IAV) NS1 protein is one of the major regulators of pathogenicity, being able to suppress innate immune response and host protein synthesis. In this study we identified the human micro RNA hsa-miR-1307-3p as a novel potent suppressor of NS1 expression and influenza virus replication. Transcriptomic analysis indicates that hsa-miR-1307-3p also negatively regulates apoptosis and promotes cell proliferation. In addition, we identified a novel mutation in the NS1 gene of A(H1N1)pdm09 strains circulating in Italy in the 2010-11 season, which enabled the virus to escape the hsa-miR-1307-3p inhibition, conferring replicative advantage to the virus in human cells. To the best of our knowledge, this is the first validation of suppression of IAV H1N1 NS1 by a human micro RNA and the first example of an escape mutation from micro RNA-mediated antiviral response for the A(H1N1)pdm09 virus.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_331,

title = {An Association Rule Mining Approach to Discover lncRNAs Expression Patterns in Cancer Datasets.},

author = {Cremaschi P and Carriero R and Astrologo S and Colì C and Lisa A and Parolo S and Bione S},

url = {10.1155/2015/146250},

doi = {10.1155/2015/146250},

year  = {2015},

date = {2015-02-14},

journal = {Biomed Research International},

volume = {2015},

pages = {146250},

abstract = {In the past few years, the role of long noncoding RNAs (lncRNAs) in tumor development and progression has been disclosed although their mechanisms of action remain to be elucidated. An important contribution to the comprehension of lncRNAs biology in cancer could be obtained through the integrated analysis of multiple expression datasets. However, the growing availability of public datasets requires new data mining techniques to integrate and describe relationship among data. In this perspective, we explored the powerness of the Association Rule Mining (ARM) approach in gene expression data analysis. By the ARM method, we performed a meta-analysis of cancer-related microarray data which allowed us to identify and characterize a set of ten lncRNAs simultaneously altered in different brain tumor datasets. The expression profiles of the ten lncRNAs appeared to be sufficient to distinguish between cancer and normal tissues. A further characterization of this lncRNAs signature through a comodulation expression analysis suggested that biological processes specific of the nervous system could be compromised.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_343,

title = {Characterization of the biological processes shaping the genetic structure of the Italian population.},

author = {Parolo S and Lisa A and Gentilini D and Di Blasio AM and Barlera S and Nicolis EB and Boncoraglio GB and Parati EA and Bione S},

url = {https://bmcgenet.biomedcentral.com/articles/10.1186/s12863-015-0293-x},

doi = {10.1186/s12863-015-0293-x.},

year  = {2015},

date = {2015-02-04},

journal = {BMC Genetics},

volume = {16},

pages = {132},

abstract = {BACKGROUND: The genetic structure of human populations is the outcome of the combined action of different processes such as demographic dynamics and natural selection. Several efforts toward the characterization of population genetic architectures and the identification of adaptation signatures were recently made. In this study, we provide a genome-wide depiction of the Italian population structure and the analysis of the major determinants of the current existing genetic variation. RESULTS: We defined and characterized 210 genomic loci associated with the first Principal Component calculated on the Italian genotypic data and correlated to the North-south genetic gradient. Using a gene-enrichment approach we identified the immune function as primarily involved in the Italian population differentiation and we described a locus on chromosome 13 showing combined evidence of North-south diversification in allele frequencies and signs of recent positive selection. In this region our bioinformatics analysis pinpointed an uncharacterized long intergenic non-coding (lincRNA), whose expression appeared specific for immune-related tissues suggesting its relevance for the immune function. CONCLUSIONS:

Our study, combining population genetic analyses with biological insights provides a description of the Italian genetic structure that in future could contribute to the evaluation of complex diseases risk in the population context.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_346,

title = {Chronic Replication Problems Impact Cell Morphology and Adhesion of DNA Ligase I Defective Cells.},

author = {Cremaschi P and Oliverio M and Leva V and Bione S and Carriero R and Mazzucco G and Palamidessi A and Scita G and Biamonti G and Montecucco A},

url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130561},

doi = {10.1371/journal.pone.0130561},

year  = {2015},

date = {2015-02-04},

journal = {Plos One},

volume = {10},

number = {7},

pages = {e0130561},

abstract = {Moderate DNA damage resulting from metabolic activities or sub-lethal doses of exogenous insults may eventually lead to cancer onset. Human 46BR.1G1 cells bear a mutation in replicative DNA ligase I (LigI) which results in low levels of replication-dependent DNA damage. This replication stress elicits a constitutive phosphorylation of the ataxia telangiectasia mutated (ATM) checkpoint kinase that fails to arrest cell cycle progression or to activate apoptosis or cell senescence. Stable transfection of wild type LigI, as in 7A3 cells, prevents DNA damage and ATM activation. Here we show that parental 46BR.1G1 and 7A3 cells differ in important features such as cell morphology, adhesion and migration. Comparison of gene expression profiles in the two cell lines detects Bio-Functional categories consistent with the morphological and migration properties of LigI deficient cells. Interestingly, ATM inhibition makes 46BR.1G1 more similar to 7A3 cells for what concerns morphology, adhesion and expression of cell-cell adhesion receptors. These observations extend the influence of the DNA damage response checkpoint pathways and unveil a role for ATM kinase activity in modulating cell biology parameters relevant to cancer progression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_368,

title = {Heritability of young- and old-onset ischaemic stroke.},

author = {Bluher A and Devan WJ and Holliday EG and Nalls M and Parolo S and Bione S and Giese AK and Boncoraglio GB and Maguire JM and Muller-Nurasyid M and Gieger C and Meschia JF and Rosand J and Rolfs A and Kittner SJ and Mitchell BD and O'Connell JR and Cheng YC},

url = {https://onlinelibrary.wiley.com/doi/full/10.1111/ene.12827},

doi = {10.1111/ene.12827},

year  = {2015},

date = {2015-11-27},

journal = {European Journal of Neurology},

volume = {22},

number = {11},

pages = {1488-1491},

abstract = {Although the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. METHODS: This analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age < 55 years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age ≥ 55 years). RESULTS: Heritabilities for young-onset stroke and old-onset stroke were estimated at 42% (±8%, P < 0.001) and 34% (±10%, P < 0.001), respectively. CONCLUSIONS: Our data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant. 2015 EAN.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}