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4 results on '"Stephanie Hampp"'

1. Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia

Author

Salih Demir, Elena Boldrin, Qian Sun, Stephanie Hampp, Eugen Tausch, Cornelia Eckert, Martin Ebinger, Rupert Handgretinger, Geertruy te Kronnie, Lisa Wiesmüller, Stephan Stilgenbauer, Galina Selivanova, Klaus-Michael Debatin, and Lüder Hinrich Meyer

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Alterations of the tumor suppressor gene TP53 are found in different cancers, in particular in carcinomas of adults. In pediatric acute lymphoblastic leukemia (ALL), TP53 mutations are infrequent but enriched at relapse. As in most cancers, mainly DNA-binding domain missense mutations are found, resulting in accumulation of mutant p53, poor therapy response, and inferior outcome. Different strategies to target mutant p53 have been developed including reactivation of p53’s wildtype function by the small molecule APR-246. We investigated TP53 mutations in cell lines and 62 B-cell precursor ALL samples and evaluated the activity of APR-246 in TP53-mutated or wildtype ALL. We identified cases with TP53 missense mutations, high (mutant) p53 expression and insensitivity to the DNA-damaging agent doxorubicin. In TP53-mutated ALL, APR-246 induced apoptosis showing strong anti-leukemia activity. APR-246 restored mutant p53 to its wildtype conformation, leading to pathway activation with induction of transcriptional targets and re-sensitization to genotoxic therapy in vitro and in vivo. In addition, induction of oxidative stress contributed to APR-246-mediated cell death. In a preclinical model of patient-derived TP53-mutant ALL, APR-246 reduced leukemia burden and synergized strongly with the genotoxic agent doxorubicin, leading to superior leukemia-free survival in vivo. Thus, targeting mutant p53 by APR-246, restoring its tumor suppressive function, seems to be an effective therapeutic strategy for this high-risk group of TP53-mutant ALL.

Published
2020
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2. Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia‐like phenotype, and no chromosome fragility

Author

Katharina Keupp, Stephanie Hampp, Annette Hübbel, Monika Maringa, Sarah Kostezka, Kerstin Rhiem, Anke Waha, Barbara Wappenschmidt, Roser Pujol, Jordi Surrallés, Rita K. Schmutzler, Lisa Wiesmüller, and Eric Hahnen

Subjects
biallelic BRCA1, early onset breast cancer, Fanconi anemia, p.Arg1699Gln, Genetics, QH426-470
Abstract

Abstract Background Biallelic BRCA1 mutations are regarded either embryonically lethal or to cause Fanconi anemia (FA), a genomic instability syndrome characterized by bone marrow failure, developmental abnormalities, and cancer predisposition. We report biallelic BRCA1 mutations c.181T > G (p.Cys61Gly) and c.5096G > A (p.Arg1699Gln) in a woman with breast cancer diagnosed at the age of 30 years. The common European founder mutation p.Cys61Gly confers high cancer risk, whereas the deleterious p.Arg1699Gln is hypomorphic and was suggested to confer intermediate cancer risk. Methods and Results Aside from significant toxicity from chemotherapy, the patient showed mild FA‐like features (e.g., short stature, microcephaly, skin hyperpigmentation). Chromosome fragility, a hallmark of FA patient cells, was not present in patient‐derived peripheral blood lymphocytes. We demonstrated that the p.Arg1699Gln mutation impairs DNA double‐strand break repair, elevates RAD51 foci levels at baseline, and compromises BRCA1 protein function in protecting from replication stress. Although the p.Arg1699Gln mutation compromises BRCA1 function, the residual activity of the p.Arg1699Gln allele likely prevents from chromosome fragility and a more severe FA phenotype. Conclusion Our data expand the clinical spectrum associated with biallelic BRCA1 mutations, ranging from embryonic lethality to a mild FA‐like phenotype and no chromosome fragility.

Published
2019
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3. The C-terminal domain of p53 orchestrates the interplay between non-covalent and covalent poly(ADP-ribosyl)ation of p53 by PARP1

Author

Karin Hauser, Annika Krüger, Pascal Rossatti, Matthias Hufnagel, Elisa Ferrando-May, Alexander Bürkle, Andrea Hartwig, Arthur Fischbach, Jan M. F. Fischer, Aswin Mangerich, Martin Stöckl, Magdalena Ganz, Stephanie Hampp, Sebastian Veith, Lisa Rank, Greta Marie Assmann, and Lisa Wiesmüller

Subjects
0301 basic medicine, Life sciences, biology, Protein domain, Poly (ADP-Ribose) Polymerase-1, Plasma protein binding, Biology, Interactome, 03 medical and health sciences, chemistry.chemical_compound, Poly ADP Ribosylation, Protein Domains, Cell Line, Tumor, ddc:570, Genetics, Humans, Molecular Biology, 030102 biochemistry & molecular biology, Adenosine diphosphate ribose, C-terminus, Cell biology, Crosstalk (biology), 030104 developmental biology, chemistry, Proteome, Tumor Suppressor Protein p53, K562 Cells, Protein Processing, Post-Translational, DNA, Protein Binding
Abstract

The post-translational modification poly(ADP-ribosyl)ation (PARylation) plays key roles in genome maintenance and transcription. Both non-covalent poly(ADP-ribose) binding and covalent PARylation control protein functions, however, it is unknown how the two modes of modification crosstalk mechanistically. Employing the tumor suppressor p53 as a model substrate, this study provides detailed insights into the interplay between non-covalent and covalent PARylation and unravels its functional significance in the regulation of p53. We reveal that the multifunctional C-terminal domain (CTD) of p53 acts as the central hub in the PARylation-dependent regulation of p53. Specifically, p53 bound to auto-PARylated PARP1 via highly specific non–covalent PAR-CTD interaction, which conveyed target specificity for its covalent PARylation by PARP1. Strikingly, fusing the p53-CTD to a protein that is normally not PARylated, renders this a target for covalent PARylation as well. Functional studies revealed that the p53–PAR interaction had substantial implications on molecular and cellular levels. Thus, PAR significantly influenced the complex p53–DNA binding properties and controlled p53 functions, with major implications on the p53-dependent interactome, transcription, and replication-associated recombination. Remarkably, this mechanism potentially also applies to other PARylation targets, since a bioinformatics analysis revealed that CTD-like regions are highly enriched in the PARylated proteome. published

Published
2018

4. DNA damage tolerance pathway involving DNA polymerase ? and the tumor suppressor p53 regulates DNA replication fork progression

Author

Helmut Pospiech, Tina Kiessling, Stephanie Hampp, Vanesa Gottifredi, Kerstin Buechle, Sabrina F. Mansilla, Lisa Wiesmüller, Jinwoo Ahn, Melanie Rall, and Jürgen Thomale

Subjects
p53, DNA Replication, 0301 basic medicine, DNA Repair, DNA polymerase II, Medizin, Eukaryotic DNA replication, nascent DNA elongation, polymerase, DNA polymerase idling, DNA damage bypass, DNA-Directed DNA Polymerase, Fork progression, Ciencias Biológicas, 03 medical and health sciences, Replication factor C, Control of chromosome duplication, Cell Line, Tumor, Replication Protein A, DNA fibers, Humans, Homologous Recombination, Replication protein A, Cells, Cultured, Multidisciplinary, DNA clamp, biology, DNA polymerase iota, DNA Helicases, DNA replication, DNA, Bioquímica y Biología Molecular, DNA Replication Fork, Molecular biology, DNA-Binding Proteins, 030104 developmental biology, PNAS Plus, DNA Polymerase iota, biology.protein, Nucleic Acid Conformation, RNA Interference, Tumor Suppressor Protein p53, K562 Cells, CIENCIAS NATURALES Y EXACTAS, DNA Damage, Transcription Factors
Abstract

DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonuclease-deficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linker-induced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress. Fil: Hampp, Stephanie. Universitat Ulm; Alemania Fil: Kiessling, Tina. Universitat Ulm; Alemania Fil: Buechle, Kerstin. Universitat Ulm; Alemania Fil: Mansilla, Sabrina Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Thomale, Jürgen. Universitat Duisburg - Essen; Alemania Fil: Rall, Melanie. Universitat Ulm; Alemania Fil: Ahn, Jinwoo. Columbia University; Estados Unidos Fil: Pospiech, Helmut. Leibniz Institute on Aging–Fritz Lipmann Institute; Alemania. University of Oulu; Finlandia Fil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Wiesmüller, Lisa. Universitat Ulm; Alemania

Published
2016

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