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Your search keyword '"Pellarin, Ilenia"' showing total 4 results
Start Over Author "Pellarin, Ilenia" Topic dna damage
4 results on '"Pellarin, Ilenia"'

1. USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity.

Author

Nespolo A, Stefenatti L, Pellarin I, Gambelli A, Rampioni Vinciguerra GL, Karimbayli J, Barozzi S, Orsenigo F, Spizzo R, Nicoloso MS, Segatto I, D'Andrea S, Bartoletti M, Lucia E, Giorda G, Canzonieri V, Puglisi F, Belletti B, Schiappacassi M, Baldassarre G, and Sonego M

Subjects
Humans, Female, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Drug Resistance, Neoplasm drug effects, Poly ADP Ribosylation, Protein Binding, Poly (ADP-Ribose) Polymerase-1 metabolism, Ubiquitination, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Ubiquitin-Specific Proteases metabolism, Ubiquitin-Specific Proteases genetics, Ovarian Neoplasms drug therapy, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Ovarian Neoplasms genetics, DNA Damage
Abstract

PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)-based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.

Published
2024
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2. The Architectural Chromatin Factor High Mobility Group A1 Enhances DNA Ligase IV Activity Influencing DNA Repair.

Author

Pellarin, Ilenia, Arnoldo, Laura, Costantini, Silvia, Pegoraro, Silvia, Ros, Gloria, Penzo, Carlotta, Triolo, Gianluca, Demarchi, Francesca, Sgarra, Riccardo, Vindigni, Alessandro, and Manfioletti, Guidalberto

Subjects
*CHROMATIN, *DNA ligases, *DNA repair, *TRANSCRIPTION factors, *GENE expression
Abstract

The HMGA1 architectural transcription factor is an oncogene overexpressed in the vast majority of human cancers. HMGA1 is a highly connected node in the nuclear molecular network and the key aspect of HMGA1 involvement in cancer development is that HMGA1 simultaneously confers cells multiple oncogenic hits, ranging from global chromatin structural and gene expression modifications up to the direct functional alterations of key cellular proteins. Interestingly, HMGA1 also modulates DNA damage repair pathways. In this work, we provide evidences linking HMGA1 with Non-Homologous End Joining DNA repair. We show that HMGA1 is in complex with and is a substrate for DNA-PK. HMGA1 enhances Ligase IV activity and it counteracts the repressive histone H1 activity towards DNA ends ligation. Moreover, breast cancer cells overexpressing HMGA1 show a faster recovery upon induction of DNA double-strand breaks, which is associated with a higher survival. These data suggest that resistance to DNA-damaging agents in cancer cells could be partially attributed to HMGA1 overexpression thus highlighting the relevance of considering HMGA1 expression levels in the selection of valuable and effective pharmacological regimens. [ABSTRACT FROM AUTHOR]

Published
2016
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3. CDK6 protects epithelial ovarian cancer from platinum‐induced death via FOXO3 regulation

Author

Delia Mezzanzanica, Monica Schiappacassi, Maura Sonego, Giorgio Giorda, Alessandra Dall'Acqua, Sara D'Andrea, Barbara Belletti, Ilenia Pellarin, Roberto Sorio, Daniela Califano, Gennaro Chiappetta, Loredana Militello, Ilenia Pellizzari, Sara Benevol, Joshua Armenia, Marina Bagnoli, Gustavo Baldassarre, Vincenzo Canzonieri, Dall'Acqua, Alessandra, Sonego, Maura, Pellizzari, Ilenia, Pellarin, Ilenia, Canzonieri, Vincenzo, D'Andrea, Sara, Benevol, Sara, Sorio, Roberto, Giorda, Giorgio, Califano, Daniela, Bagnoli, Marina, Militello, Loredana, Mezzanzanica, Delia, Chiappetta, Gennaro, Armenia, Joshua, Belletti, Barbara, Schiappacassi, Monica, and Baldassarre, Gustavo

Subjects
0301 basic medicine, endocrine system diseases, Pyridines, Ataxia Telangiectasia Mutated Proteins, Carcinoma, Ovarian Epithelial, Piperazines, Mice, platinum sensitivity, Neoplasms, Glandular and Epithelial, Research Articles, Cancer, Ovarian Neoplasms, Cell Death, biology, Forkhead Box Protein O3, ATR, CDK6, FOXO3, ovarian cancer, Primary tumor, female genital diseases and pregnancy complications, Molecular Medicine, Female, Research Article, Programmed cell death, DNA damage, Primary Cell Culture, Urogenital System, Mice, Nude, Antineoplastic Agents, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Gene silencing, Pharmacology & Drug Discovery, Protein Kinase Inhibitors, Transcription factor, Platinum, Cyclin-Dependent Kinase 6, medicine.disease, Survival Analysis, Xenograft Model Antitumor Assays, 030104 developmental biology, Apoptosis, Immunology, biology.protein, Cancer research, Cyclin-dependent kinase 6, Ovarian cancer, DNA Damage
Abstract

Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum‐based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro , in xenografts in vivo , and in primary tumor cells derived from platinum‐treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.

Published
2017

4. The Architectural Chromatin Factor High Mobility Group A1 Enhances DNA Ligase IV Activity Influencing DNA Repair

Author

Francesca Demarchi, Guidalberto Manfioletti, Ilenia Pellarin, Riccardo Sgarra, Silvia Costantini, Laura Arnoldo, Alessandro Vindigni, Gloria Ros, Carlotta Penzo, Gianluca Triolo, Silvia Pegoraro, Pellarin, Ilenia, Arnoldo, Laura, Costantini, S, Pegoraro, Silvia, Ros, Gloria, Penzo, Carlotta, Triolo, G, Demarchi, F, Sgarra, Riccardo, Vindigni, A, and Manfioletti, Guidalberto

Subjects
0301 basic medicine, DNA Repair, lcsh:Medicine, Biochemistry, Substrate Specificity, Ligases, Histones, DNA Ligase ATP, 0302 clinical medicine, Cancer epigenetics, HMGA1a Protein, Post-Translational Modification, Phosphorylation, Ligation Assay, lcsh:Science, Chromatography, High Pressure Liquid, chemistry.chemical_classification, Multidisciplinary, biology, DNA repair protein XRCC4, Recombinant Proteins, Chromatin, Enzymes, Nucleic acids, Architectural transcription factors, 030220 oncology & carcinogenesis, MCF-7 Cells, DNA mismatch repair, Comet Assay, Research Article, DNA repair, Research and Analysis Methods, Non-Homologous End Joining, 03 medical and health sciences, breast cancer, Cell Line, Tumor, DNA-binding proteins, Genetics, Humans, Molecular Biology Techniques, Molecular Biology, Ku Autoantigen, DNA double-stranded breaks, Architectural transcription factors, DNA repair, DNA double-stranded breaks, breast cancer, DNA ligase, Molecular Biology Assays and Analysis Techniques, lcsh:R, HMGA2 Protein, Biology and Life Sciences, Proteins, DNA, Proliferating cell nuclear antigen, 030104 developmental biology, chemistry, Microscopy, Fluorescence, biology.protein, Cancer research, Enzymology, DNA damage, lcsh:Q, Nucleotide excision repair
Abstract

The HMGA1 architectural transcription factor is an oncogene overexpressed in the vast majority of human cancers. HMGA1 is a highly connected node in the nuclear molecular network and the key aspect of HMGA1 involvement in cancer development is that HMGA1 simultaneously confers cells multiple oncogenic hits, ranging from global chromatin structural and gene expression modifications up to the direct functional alterations of key cellular proteins. Interestingly, HMGA1 also modulates DNA damage repair pathways. In this work, we provide evidences linking HMGA1 with Non-Homologous End Joining DNA repair. We show that HMGA1 is in complex with and is a substrate for DNA-PK. HMGA1 enhances Ligase IV activity and it counteracts the repressive histone H1 activity towards DNA ends ligation. Moreover, breast cancer cells overexpressing HMGA1 show a faster recovery upon induction of DNA double-strand breaks, which is associated with a higher survival. These data suggest that resistance to DNA-damaging agents in cancer cells could be partially attributed to HMGA1 overexpression thus highlighting the relevance of considering HMGA1 expression levels in the selection of valuable and effective pharmacological regimens.

Published
2016

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