11 results on '"Damizia, Michela"'
Search Results
2. Importin-β/karyopherin-β1 modulates mitotic microtubule function and taxane sensitivity in cancer cells via its nucleoporin-binding region
- Author
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Verrico, Annalisa, Rovella, Paola, Di Francesco, Laura, Damizia, Michela, Staid, David Sasah, Le Pera, Loredana, Schininà, M. Eugenia, and Lavia, Patrizia
- Published
- 2020
- Full Text
- View/download PDF
3. Distinct Mitotic Functions of Nucleolar and Spindle-Associated Protein 1 (NuSAP1) Are Controlled by Two Consensus SUMOylation Sites.
- Author
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Damizia, Michela, Altieri, Ludovica, Costanzo, Vincenzo, and Lavia, Patrizia
- Subjects
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NUCLEAR proteins , *CHROMOSOME segregation , *SMALL ubiquitin-related modifier proteins , *SITE-specific mutagenesis , *PEPTIDES , *UBIQUITINATION - Abstract
Nucleolar and Spindle-Associated Protein 1 (NuSAP1) is an important mitotic regulator, implicated in control of mitotic microtubule stability and chromosome segregation. NuSAP1 regulates these processes by interacting with several protein partners. Its abundance, activity and interactions are therefore tightly regulated during mitosis. Protein conjugation with SUMO (Small Ubiquitin-like MOdifier peptide) is a reversible post-translational modification that modulates rapid changes in the structure, interaction(s) and localization of proteins. NuSAP1 was previously found to interact with RANBP2, a nucleoporin with SUMO ligase and SUMO-stabilizing activity, but how this interaction affects NuSAP1 activity has remained elusive. Here, we show that NuSAP1 interacts with RANBP2 and forms proximity ligation products with SUMO2/3 peptides in a RANBP2-dependent manner at key mitotic sites. A bioinformatic search identified two putative SUMO consensus sites in NuSAP1, within the DNA-binding and the microtubule-binding domains, respectively. Site-specific mutagenesis, and mitotic phenotyping in cell lines expressing each NuSAP1 mutant version, revealed selective roles of each individual site in control of NuSAP1 localization and in generation of specific mitotic defects and distinct fates in daughter cells. These results identify therefore two new regulatory sites for NuSAP1 functions and implicate RANBP2 in control of NuSAP1 activity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. Rio1 downregulates centromeric RNA levels to promote the timely assembly of structurally fit kinetochores.
- Author
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Smurova, Ksenia, Damizia, Michela, Irene, Carmela, Stancari, Stefania, Berto, Giovanna, Perticari, Giulia, Iacovella, Maria Giuseppina, D'Ambrosio, Ilaria, Giubettini, Maria, Philippe, Réginald, Baggio, Chiara, Callegaro, Elisabetta, Casagranda, Andrea, Corsini, Alessandro, Polese, Vincenzo Gentile, Ricci, Anna, Dassi, Erik, and De Wulf, Peter
- Subjects
RNA polymerase II ,RNA ,PROTEIN kinases ,CENTROMERE ,CHROMOSOMES ,HISTONES - Abstract
Kinetochores assemble on centromeres via histone H3 variant CENP-A and low levels of centromere transcripts (cenRNAs). The latter are ensured by the downregulation of RNA polymerase II (RNAPII) activity, and cenRNA turnover by the nuclear exosome. Using S. cerevisiae, we now add protein kinase Rio1 to this scheme. Yeast cenRNAs are produced either as short (median lengths of 231 nt) or long (4458 nt) transcripts, in a 1:1 ratio. Rio1 limits their production by reducing RNAPII accessibility and promotes cenRNA degradation by the 5'−3'exoribonuclease Rat1. Rio1 similarly curtails the concentrations of noncoding pericenRNAs. These exist as short transcripts (225 nt) at levels that are minimally two orders of magnitude higher than the cenRNAs. In yeast depleted of Rio1, cen- and pericenRNAs accumulate, CEN nucleosomes and kinetochores misform, causing chromosome instability. The latter phenotypes are also observed with human cells lacking orthologue RioK1, suggesting that CEN regulation by Rio1/RioK1 is evolutionary conserved. Kinetochores assemble on centromeres via histone H3 variant CENP-A and low levels of centromere transcripts (cenRNAs). Here the authors show the Rio1 kinase limits cenRNA production by reducing RNAPII accessibility and promotes cenRNA degradation by the 5'− 3'exoribonuclease Rat1. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. Aurora B SUMOylation Is Restricted to Centromeres in Early Mitosis and Requires RANBP2.
- Author
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Di Cesare, Erica, Moroni, Sara, Bartoli, Jessica, Damizia, Michela, Giubettini, Maria, Koerner, Carolin, Krenn, Veronica, Musacchio, Andrea, and Lavia, Patrizia
- Subjects
CENTROMERE ,AURORA kinases ,MITOSIS ,B cells ,PROTEIN-protein interactions - Abstract
Conjugation with the small ubiquitin-like modifier (SUMO) modulates protein interactions and localisation. The kinase Aurora B, a key regulator of mitosis, was previously identified as a SUMOylation target in vitro and in assays with overexpressed components. However, where and when this modification genuinely occurs in human cells was not ascertained. Here, we have developed intramolecular Proximity Ligation Assays (PLA) to visualise SUMO-conjugated Aurora B in human cells in situ. We visualised Aurora B-SUMO products at centromeres in prometaphase and metaphase, which declined from anaphase onwards and became virtually undetectable at cytokinesis. In the mitotic window in which Aurora B/SUMO products are abundant, Aurora B co-localised and interacted with NUP358/RANBP2, a nucleoporin with SUMO ligase and SUMO-stabilising activity. Indeed, in addition to the requirement for the previously identified PIAS3 SUMO ligase, we found that NUP358/RANBP2 is also implicated in Aurora B-SUMO PLA product formation and centromere localisation. In summary, SUMOylation marks a distinctive window of Aurora B functions at centromeres in prometaphase and metaphase while being dispensable for functions exerted in cytokinesis, and RANBP2 contributes to this control, adding a novel layer to modulation of Aurora B functions during mitosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases.
- Author
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Degrassi, Francesca, Damizia, Michela, and Lavia, Patrizia
- Subjects
- *
MITOSIS , *MICROCEPHALY , *CHROMOSOME segregation , *CELL morphology , *SOMATIC cells , *CENTRAL nervous system - Abstract
Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
7. Importin-ß and CRM1 control a RANBP2 spatiotemporal switch essential for mitotic kinetochore function.
- Author
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Gilistro, Eugenia, de Turris, Valeria, Damizia, Michela, Verrico, Annalisa, Moroni, Sara, De Santis, Riccardo, Rosa, Alessandro, and Lavia, Patrizia
- Subjects
SMALL ubiquitin-related modifier proteins ,PROTEINS ,NUCLEOPORINS ,GUANOSINE triphosphatase ,MITOSIS ,NUCLEAR transport ,DNA topoisomerase II - Abstract
Protein conjugation with small ubiquitin-related modifier (SUMO) is a post-translational modification that modulates protein interactions and localisation. RANBP2 is a large nucleoporin endowed with SUMO E3 ligase and SUMO-stabilising activity, and is implicated in some cancer types. RANBP2 is part of a larger complex, consisting of SUMO-modified RANGAP1, the GTP-hydrolysis activating factor for the GTPase RAN. During mitosis, the RANBP2-SUMO-RANGAP1 complex localises to the mitotic spindle and to kinetochores after microtubule attachment. Here, we address the mechanisms that regulate this localisation and how they affect kinetochore functions. Using proximity ligation assays, we find that nuclear transport receptors importin-ß and CRM1 play essential roles in localising the RANBP2-SUMO-RANGAP1 complex away from, or at kinetochores, respectively. Using newly generated inducible cell lines, we show that overexpression of nuclear transport receptors affects the timing of RANBP2 localisation in opposite ways. Concomitantly, kinetochore functions are also affected, including the accumulation of SUMO-conjugated topoisomerase-IIa and stability of kinetochore fibres. These results delineate a novel mechanism through which nuclear transport receptors govern the functional state of kinetochores by regulating the timely deposition of RANBP2. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
8. Circular RNA ZNF609/CKAP5 mRNA interaction regulates microtubule dynamics and tumorigenicity.
- Author
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Rossi, Francesca, Beltran, Manuel, Damizia, Michela, Grelloni, Chiara, Colantoni, Alessio, Setti, Adriano, Di Timoteo, Gaia, Dattilo, Dario, Centrón-Broco, Alvaro, Nicoletti, Carmine, Fanciulli, Maurizio, Lavia, Patrizia, and Bozzoni, Irene
- Subjects
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CIRCULAR RNA , *MICROTUBULES , *MESSENGER RNA , *NUCLEIC acids , *RNA-binding proteins , *TUMOR growth - Abstract
Circular RNAs (circRNAs) are widely expressed in eukaryotes and are regulated in many biological processes. Although several studies indicate their activity as microRNA (miRNA) and protein sponges, little is known about their ability to directly control mRNA homeostasis. We show that the widely expressed circZNF609 directly interacts with several mRNAs and increases their stability and/or translation by favoring the recruitment of the RNA-binding protein ELAVL1. Particularly, the interaction with CKAP5 mRNA, which interestingly overlaps the back-splicing junction, enhances CKAP5 translation, regulating microtubule function in cancer cells and sustaining cell-cycle progression. Finally, we show that circZNF609 downregulation increases the sensitivity of several cancer cell lines to different microtubule-targeting chemotherapeutic drugs and that locked nucleic acid (LNA) protectors against the pairing region on circZNF609 phenocopy such effects. These data set an example of how the small effects tuned by circZNF609 /CKAP5 mRNA interaction might have a potent output in tumor growth and drug response. [Display omitted] • circZNF609 interacts with CKAP5 , UPF2 , and SRRM1 mRNAs in vivo • circZNF609-mRNA interaction increases ELAVL1 loading on the mRNAs • ELAVL1 loading by circZNF609 regulates stability and translation of its targets • CAKP5 regulation alters MT dynamics, sensitizing cells to chemotherapeutic drugs In this article, Rossi et al. provide an interesting mechanism in which circZNF609-mRNA interaction increases translation, and among them, CKAP5 is a key factor in microtubule dynamics stability. The authors show how the disruption of RNA-RNA interactions is able to alter microtubule dynamics, sensitizing rhabdomyosarcoma cells to chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
9. Non-transport roles of nuclear import receptors: In need of the right balance.
- Author
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Damizia M, Altieri L, and Lavia P
- Abstract
Nuclear import receptors ensure the recognition and transport of proteins across the nuclear envelope into the nucleus. In addition, as diverse processes as mitosis, post-translational modifications at mitotic exit, ciliogenesis, and phase separation, all share a common need for regulation by nuclear import receptors - particularly importin beta-1 and importin beta-2/transportin - independent on nuclear import. In particular, 1) nuclear import receptors regulate the mitotic spindle after nuclear envelope breakdown, 2) they shield cargoes from unscheduled ubiquitination, regulating their timely proteolysis; 3) they regulate ciliary factors, crucial to cell communications and tissue architecture during development; and 4) they prevent phase separation of toxic proteins aggregates in neurons. The balance of nuclear import receptors to cargoes is critical in all these processes, albeit in opposite directions: overexpression of import receptors, as often found in cancer, inhibits cargoes and impairs downstream processes, motivating the therapeutic design of specific inhibitors. On the contrary, elevated expression is beneficial in neuronal contexts, where nuclear import receptors are regarded as potential therapeutic tools in counteracting the formation of aggregates that may cause neurodegeneration. This paradox demonstrates the amplitude of nuclear import receptors-dependent functions in different contexts and adds complexity in considering their therapeutic implications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Damizia, Altieri and Lavia.)
- Published
- 2022
- Full Text
- View/download PDF
10. The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases.
- Author
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Degrassi F, Damizia M, and Lavia P
- Subjects
- Cell Proliferation genetics, Chromosome Segregation genetics, Chromosome Segregation physiology, Humans, Kinetochores physiology, Microcephaly metabolism, Mitosis physiology, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders metabolism, Spindle Apparatus genetics, Kinetochores metabolism, Microcephaly genetics, Spindle Apparatus metabolism
- Abstract
Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system.
- Published
- 2019
- Full Text
- View/download PDF
11. Importin-β and CRM1 control a RANBP2 spatiotemporal switch essential for mitotic kinetochore function.
- Author
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Gilistro E, de Turris V, Damizia M, Verrico A, Moroni S, De Santis R, Rosa A, and Lavia P
- Subjects
- GTPase-Activating Proteins genetics, GTPase-Activating Proteins metabolism, HeLa Cells, Humans, Karyopherins genetics, Molecular Chaperones genetics, Nuclear Pore Complex Proteins genetics, Receptors, Cytoplasmic and Nuclear genetics, SUMO-1 Protein genetics, SUMO-1 Protein metabolism, beta Karyopherins genetics, Exportin 1 Protein, Karyopherins metabolism, Kinetochores metabolism, Molecular Chaperones metabolism, Nuclear Pore Complex Proteins metabolism, Receptors, Cytoplasmic and Nuclear metabolism, beta Karyopherins metabolism
- Abstract
Protein conjugation with small ubiquitin-related modifier (SUMO) is a post-translational modification that modulates protein interactions and localisation. RANBP2 is a large nucleoporin endowed with SUMO E3 ligase and SUMO-stabilising activity, and is implicated in some cancer types. RANBP2 is part of a larger complex, consisting of SUMO-modified RANGAP1, the GTP-hydrolysis activating factor for the GTPase RAN. During mitosis, the RANBP2-SUMO-RANGAP1 complex localises to the mitotic spindle and to kinetochores after microtubule attachment. Here, we address the mechanisms that regulate this localisation and how they affect kinetochore functions. Using proximity ligation assays, we find that nuclear transport receptors importin-β and CRM1 play essential roles in localising the RANBP2-SUMO-RANGAP1 complex away from, or at kinetochores, respectively. Using newly generated inducible cell lines, we show that overexpression of nuclear transport receptors affects the timing of RANBP2 localisation in opposite ways. Concomitantly, kinetochore functions are also affected, including the accumulation of SUMO-conjugated topoisomerase-IIα and stability of kinetochore fibres. These results delineate a novel mechanism through which nuclear transport receptors govern the functional state of kinetochores by regulating the timely deposition of RANBP2., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
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