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Article ; Online: Phosphorylation status of MUS81 is a modifier of Olaparib sensitivity in BRCA2-deficient cells.

Blandino, Francesca / Malacaria, Eva / Figlioli, Carolina / Noto, Alessandro / Pugliese, Giusj Monia / Franchitto, Annapaola / Pichierri, Pietro

Nucleic acids research

2023 Volume 51, Issue 13, Page(s) 6723–6737

Abstract: The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different ... ...

Abstract	The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different MUS81 complexes in mammalian cells that act in M- or S-phase, whether and how the PARPi sensitivity of BRCA2-deficient cells is affected by loss of MUS81 function is unclear. Here, using a mutant of MUS81 that impairs its function in M-phase, we show that viability of BRCA2-deficient cells but not their PARPi sensitivity requires a fully-functional MUS81 complex in mitosis. In contrast, expression of a constitutively-active MUS81 is sufficient to confer PARPi resistance. From a mechanistic point of view, our data indicate that deregulated action of the mitotic active form of MUS81 in S-phase leads to the cleavage of stalled replication forks before their reversal, bypassing fork deprotection, and engaging a Polθ-dependent DSBs repair. Collectively, our findings describe a novel mechanism leading to PARPi resistance that involves unscheduled MUS81-dependent cleavage of intact, unreversed replication forks. Since this cleavage occurs mimicking the phosphorylated status of S87 of MUS81, our data suggest that hyperphosphorylation of this residue in S-phase might represent a novel biomarker to identify resistance to PARPi.
MeSH term(s)	Animals ; DNA Replication ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Endonucleases/metabolism ; Mammals/metabolism ; Phosphorylation ; Antineoplastic Agents/metabolism
Chemical Substances	DNA-Binding Proteins ; Endonucleases (EC 3.1.-) ; olaparib (WOH1JD9AR8) ; Antineoplastic Agents
Language	English
Publishing date	2023-05-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad470
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Article: Combining Mass Spectrometry-Based Phosphoproteomics with a Network-Based Approach to Reveal FLT3-Dependent Mechanisms of Chemoresistance.

Pugliese, Giusj Monia / Latini, Sara / Massacci, Giorgia / Perfetto, Livia / Sacco, Francesca

Proteomes

2021 Volume 9, Issue 2

Abstract: FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor clinical outcome, relapse and chemotherapeutic resistance. Elucidating the molecular mechanisms underlying FLT3-dependent ... ...

Abstract	FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor clinical outcome, relapse and chemotherapeutic resistance. Elucidating the molecular mechanisms underlying FLT3-dependent pathogenesis and drug resistance is a crucial goal of biomedical research. Given the complexity and intricacy of protein signaling networks, deciphering the molecular basis of FLT3-driven drug resistance requires a systems approach. Here we discuss how the recent advances in mass spectrometry (MS)-based (phospho) proteomics and multiparametric analysis accompanied by emerging computational approaches offer a platform to obtain and systematically analyze cell-specific signaling networks and to identify new potential therapeutic targets.
Language	English
Publishing date	2021-04-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720995-7
ISSN	2227-7382
ISSN	2227-7382
DOI	10.3390/proteomes9020019
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Article ; Online: Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction.

Latini, Sara / Venafra, Veronica / Massacci, Giorgia / Bica, Valeria / Graziosi, Simone / Pugliese, Giusj Monia / Iannuccelli, Marta / Frioni, Filippo / Minnella, Gessica / Marra, John Donald / Chiusolo, Patrizia / Pepe, Gerardo / Helmer Citterich, Manuela / Mougiakakos, Dimitros / Böttcher, Martin / Fischer, Thomas / Perfetto, Livia / Sacco, Francesca

eLife

2024 Volume 12

Abstract: Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical ... ...

Abstract	Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.
MeSH term(s)	Humans ; Signal Transduction ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; MAP Kinase Signaling System ; Cell Line ; Drug Resistance ; fms-Like Tyrosine Kinase 3/genetics
Chemical Substances	FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
Language	English
Publishing date	2024-04-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.90532
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Article ; Online: Impact of FLT3-ITD location on cytarabine sensitivity in AML: a network-based approach.

Pugliese, Giusj Monia / Venafra, Veronica / Bica, Valeria / Massacci, Giorgia / Latini, Sara / Graziosi, Simone / Fischer, Thomas / Mougiakakos, Dimitrios / Boettcher, Martin / Perfetto, Livia / Sacco, Francesca

Leukemia

2023 Volume 37, Issue 5, Page(s) 1151–1155

MeSH term(s)	Humans ; Cytarabine/pharmacology ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Cell Line, Tumor ; fms-Like Tyrosine Kinase 3/genetics ; Mutation
Chemical Substances	Cytarabine (04079A1RDZ) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; FLT3 protein, human (EC 2.7.10.1)
Language	English
Publishing date	2023-03-25
Publishing country	England
Document type	Research Support, Non-U.S. Gov't ; Letter
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-01881-5
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Article ; Online: A key role of the WEE1-CDK1 axis in mediating TKI-therapy resistance in FLT3-ITD positive acute myeloid leukemia patients.

Massacci, Giorgia / Venafra, Veronica / Latini, Sara / Bica, Valeria / Pugliese, Giusj Monia / Graziosi, Simone / Klingelhuber, Felix / Krahmer, Natalie / Fischer, Thomas / Mougiakakos, Dimitrios / Boettcher, Martin / Perfetto, Livia / Sacco, Francesca

Leukemia

2022 Volume 37, Issue 2, Page(s) 288–297

Abstract: The insertion site of the internal tandem duplications (ITDs) in the FLT3 gene affects the sensitivity to tyrosine kinase inhibitors (TKIs) therapy in acute myeloid leukemia (AML). Patients with the ITD in the tyrosine kinase domain lack effective ... ...

Abstract	The insertion site of the internal tandem duplications (ITDs) in the FLT3 gene affects the sensitivity to tyrosine kinase inhibitors (TKIs) therapy in acute myeloid leukemia (AML). Patients with the ITD in the tyrosine kinase domain lack effective therapeutic options. Here, to identify genotype-driven strategies increasing the TKI therapy efficacy, we developed SignalingProfiler, a strategy supporting the integration of high-sensitive mass spectrometry-based (phospho)proteomics, RNA sequencing datasets with literature-derived signaling networks. The approach generated FLT3-ITD genotype-specific predictive models and revealed a conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, pharmacological inhibition of the WEE1 kinase synergizes and strengthens the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. Finally, we propose a new molecular mechanism of TKIs resistance in AML and suggest the combination of WEE1 inhibitor and TKI as a therapeutic option to improve patients clinical outcome.
MeSH term(s)	Humans ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Drug Resistance, Neoplasm/genetics ; Cell Line ; Signal Transduction ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/metabolism ; Mutation ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; CDC2 Protein Kinase/pharmacology
Chemical Substances	Protein Kinase Inhibitors ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; FLT3 protein, human (EC 2.7.10.1) ; WEE1 protein, human (EC 2.7.10.2) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Cell Cycle Proteins ; CDK1 protein, human (EC 2.7.11.22) ; CDC2 Protein Kinase (EC 2.7.11.22)
Language	English
Publishing date	2022-12-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-022-01785-w
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Article: A Resource for the Network Representation of Cell Perturbations Caused by SARS-CoV-2 Infection

Perfetto, Livia / Micarelli, Elisa / Iannuccelli, Marta / Lo Surdo, Prisca / Giuliani, Giulio / Latini, Sara / Pugliese, Giusj Monia / Massacci, Giorgia / Vumbaca, Simone / Riccio, Federica / Fuoco, Claudia / Paoluzi, Serena / Castagnoli, Luisa / Cesareni, Gianni / Licata, Luana / Sacco, Francesca

Genes. 2021 Mar. 22, v. 12, no. 3

2021

Abstract: The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted drugs is held back due to a limited understanding of the ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted drugs is held back due to a limited understanding of the molecular mechanisms underlying the perturbation of cell physiology observed after viral infection. Recently, several approaches, aimed at identifying cellular proteins that may contribute to COVID-19 pathology, have been reported. Albeit valuable, this information offers limited mechanistic insight as these efforts have produced long lists of cellular proteins, the majority of which are not annotated to any cellular pathway. We have embarked in a project aimed at bridging this mechanistic gap by developing a new bioinformatic approach to estimate the functional distance between a subset of proteins and a list of pathways. A comprehensive literature search allowed us to annotate, in the SIGNOR 2.0 resource, causal information underlying the main molecular mechanisms through which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses affect the host–cell physiology. Next, we developed a new strategy that enabled us to link SARS-CoV-2 interacting proteins to cellular phenotypes via paths of causal relationships. Remarkably, the extensive information about inhibitors of signaling proteins annotated in SIGNOR 2.0 makes it possible to formulate new potential therapeutic strategies. The proposed approach, which is generally applicable, generated a literature-based causal network that can be used as a framework to formulate informed mechanistic hypotheses on COVID-19 etiology and pathology.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; bioinformatics ; cell physiology ; etiology ; pandemic ; physiology ; therapeutics
Language	English
Dates of publication	2021-0322
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12030450
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Rad52 prevents excessive replication fork reversal and protects from nascent strand degradation.

Malacaria, Eva / Pugliese, Giusj Monia / Honda, Masayoshi / Marabitti, Veronica / Aiello, Francesca Antonella / Spies, Maria / Franchitto, Annapaola / Pichierri, Pietro

Nature communications

2019 Volume 10, Issue 1, Page(s) 1412

Abstract: Stabilisation of stalled replication forks prevents excessive fork reversal and their pathological degradation, which can undermine genome integrity. Here we investigate a physiological role of RAD52 at stalled replication forks by using human cell ... ...

Abstract	Stabilisation of stalled replication forks prevents excessive fork reversal and their pathological degradation, which can undermine genome integrity. Here we investigate a physiological role of RAD52 at stalled replication forks by using human cell models depleted of RAD52, a specific small-molecule inhibitor of the RAD52-ssDNA interaction, in vitro and single-molecule analyses. We demonstrate that RAD52 prevents excessive degradation of reversed replication forks by MRE11. Mechanistically, RAD52 binds to the stalled replication fork, promotes its occlusion and counteracts loading of SMARCAL1 in vitro and in vivo. Loss of the RAD52 function results in a slightly-defective replication restart, persistence of under-replicated regions and chromosome instability. Moreover, the RAD52-inhibited cells rely on RAD51 for completion of replication and viability upon replication arrest. Collectively, our data suggest an unexpected gatekeeper mechanism by which RAD52 limits excessive remodelling of stalled replication forks, thus indirectly assisting RAD51 and BRCA2 in protecting forks from unscheduled degradation and preventing genome instability.
MeSH term(s)	Cell Line ; DNA Damage ; DNA Helicases/metabolism ; DNA Replication ; DNA, Single-Stranded/metabolism ; Genomic Instability ; Humans ; MRE11 Homologue Protein/metabolism ; Models, Biological ; Rad51 Recombinase ; Rad52 DNA Repair and Recombination Protein/metabolism
Chemical Substances	DNA, Single-Stranded ; RAD52 protein, human ; Rad52 DNA Repair and Recombination Protein ; Rad51 Recombinase (EC 2.7.7.-) ; SMARCAL1 protein, human (EC 2.7.7.-) ; MRE11 Homologue Protein (EC 3.1.-) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2019-03-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-09196-9
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Article ; Online: Author Correction: Rad52 prevents excessive replication fork reversal and protects from nascent strand degradation.

Malacaria, Eva / Pugliese, Giusj Monia / Honda, Masayoshi / Marabitti, Veronica / Aiello, Francesca Antonella / Spies, Maria / Franchitto, Annapaola / Pichierri, Pietro

Nature communications

2019 Volume 10, Issue 1, Page(s) 2023

Abstract: The original version of this Article contained an error in Fig. 2. The immunofluorescence images in panel d were inadvertently replaced with duplicates of those in panel c during final assembly of the figure. This has been corrected in the PDF and HTML ... ...

Abstract	The original version of this Article contained an error in Fig. 2. The immunofluorescence images in panel d were inadvertently replaced with duplicates of those in panel c during final assembly of the figure. This has been corrected in the PDF and HTML versions of the Article.
Language	English
Publishing date	2019-05-01
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-10072-9
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Article ; Online: Inducible SMARCAL1 knockdown in iPSC reveals a link between replication stress and altered expression of master differentiation genes.

Pugliese, Giusj Monia / Salaris, Federico / Palermo, Valentina / Marabitti, Veronica / Morina, Nicolò / Rosa, Alessandro / Franchitto, Annapaola / Pichierri, Pietro

Disease models & mechanisms

2019 Volume 12, Issue 10

Abstract: Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to ... ...

Abstract	Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to explain the pathophysiology of the disease; however, the mechanism by which
MeSH term(s)	Cell Differentiation/genetics ; Cell Lineage ; DNA Damage/genetics ; DNA Helicases/metabolism ; DNA Repair/genetics ; DNA Replication/genetics ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Phosphorylation ; S Phase ; Stress, Physiological/genetics ; Transcription, Genetic
Chemical Substances	SMARCAL1 protein, human (EC 2.7.7.-) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2019-10-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1754-8411
ISSN (online)	1754-8411
DOI	10.1242/dmm.039487
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Article ; Online: A Resource for the Network Representation of Cell Perturbations Caused by SARS-CoV-2 Infection.

Genes

2021 Volume 12, Issue 3

Abstract	The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted drugs is held back due to a limited understanding of the molecular mechanisms underlying the perturbation of cell physiology observed after viral infection. Recently, several approaches, aimed at identifying cellular proteins that may contribute to COVID-19 pathology, have been reported. Albeit valuable, this information offers limited mechanistic insight as these efforts have produced long lists of cellular proteins, the majority of which are not annotated to any cellular pathway. We have embarked in a project aimed at bridging this mechanistic gap by developing a new bioinformatic approach to estimate the functional distance between a subset of proteins and a list of pathways. A comprehensive literature search allowed us to annotate, in the SIGNOR 2.0 resource, causal information underlying the main molecular mechanisms through which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses affect the host-cell physiology. Next, we developed a new strategy that enabled us to link SARS-CoV-2 interacting proteins to cellular phenotypes via paths of causal relationships. Remarkably, the extensive information about inhibitors of signaling proteins annotated in SIGNOR 2.0 makes it possible to formulate new potential therapeutic strategies. The proposed approach, which is generally applicable, generated a literature-based causal network that can be used as a framework to formulate informed mechanistic hypotheses on COVID-19 etiology and pathology.
MeSH term(s)	Autophagy/genetics ; COVID-19/genetics ; COVID-19/metabolism ; COVID-19/pathology ; COVID-19/virology ; Gene Ontology ; Gene Regulatory Networks ; Host Microbial Interactions/genetics ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/virology ; Proteome ; PubMed ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; SARS-CoV-2/pathogenicity ; Signal Transduction/genetics
Chemical Substances	Proteome
Language	English
Publishing date	2021-03-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12030450
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