De-ubiquitination of SAMHD1 by USP7 promotes DNA damage repair to overcome oncogenic stress and affect chemotherapy sensitivity

Oncogene, Journal Year: 2023, Volume and Issue: 42(22), P. 1843 - 1856

Published: April 20, 2023

Abstract Oncogenic stress induces DNA damage repair (DDR) that permits escape from mitotic catastrophe and allows early precursor lesions during the evolution of cancer. SAMHD1, a dNTPase protecting cells viral infections, has been recently found to participate in process. However, its role tumorigenesis remains largely unknown. Here, we show SAMHD1 is up-regulated early-stage human carcinoma tissues cell lines under oxidative or genotoxic insults. We further demonstrate de-ubiquitinating enzyme USP7 interacts with de-ubiquitinates it at lysine 421, thus stabilizing protein expression for interaction CtIP DDR, which promotes tumor survival stress. Furthermore, levels positively correlates various carcinomas, associated an unfavorable outcome patients who underwent chemotherapy. Moreover, inhibitor sensitizes chemotherapeutic agents by decreasing vitro vivo. These findings suggest de-ubiquitination DDR overcome oncogenic affect chemotherapy sensitivity.

Language: Английский

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SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Autoimmunity, Journal Year: 2018, Volume and Issue: 51(3), P. 96 - 110

Published: March 27, 2018

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a deoxynucleotide triphosphate (dNTP) hydrolase that plays an important role in the homeostatic balance of cellular dNTPs. Its emerging as effector innate immunity affirmed by mutations SAMHD1 gene cause severe autoimmune disease, Aicardi–Goutieres syndrome (AGS) are linked to cancer. Additionally, functions restriction factor for retroviruses, such HIV. Here, we review current biochemical biological properties enzyme including its structure, activity, regulation post-translational modifications context function. We outline open questions regarding biology whose answers will be understanding function regulator cell cycle progression, genomic integrity, autoimmunity.

Language: Английский

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With me or against me: Tumor suppressor and drug resistance activities of SAMHD1

Experimental Hematology, Journal Year: 2017, Volume and Issue: 52, P. 32 - 39

Published: May 12, 2017

Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) is a (deoxy)guanosine triphosphate (dGTP/GTP)-activated deoxyribonucleoside (dNTP) triphosphohydrolase involved in cellular dNTP homoeostasis. Mutations SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). also limits cells' permissiveness to infection diverse viruses, including human immunodeficiency virus (HIV-1), controls endogenous retroviruses. Increasing evidence supports role of as tumor suppressor. However, can act resistance factor nucleoside-based chemotherapies by hydrolyzing their active metabolites, thereby reducing response various malignancies these anticancer drugs. Hence, informed cancer therapies must take into account ambiguous properties both an inhibitor uncontrolled proliferation limiting efficacy treatments. Here, we provide that double-edged sword for patients acute myelogenous leukemia (AML). Our time-dependent analyses The Cancer Genome Atlas (TCGA) AML cohort indicate high expression SAMHD1, even though it critically high-dose ara-C therapy, might be more favorable progression.

Language: Английский

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Profiling the proteomic inflammatory state of human astrocytes using DIA mass spectrometry

Journal of Neuroinflammation, Journal Year: 2018, Volume and Issue: 15(1)

Published: Nov. 30, 2018

Astrocytes are the most abundant cells in central nervous system and responsible for a wide range of functions critical to normal neuronal development, synapse formation, blood-brain barrier regulation, brain homeostasis. They also actively involved initiating perpetuating neuroinflammatory responses. However, information about their proteomic phenotypes under inflammation is currently limited.Data-independent acquisition mass spectrometry was applied extensively characterize profile more than 4000 proteins immortalized human fetal astrocytes distinct inflammatory conditions induced by TNF, IL-1β, LPS, while multiplex immunoassay-based screening used quantify cytokines released these conditions. Then, immunocytochemistry western blotting were verify activation canonical non-canonical NF-κB upon exposure different stimuli. Finally, an vitro model consisting co-culture primary microvascular endothelial response LPS complex system.We reported on set 186 whose levels significantly modulated LPS. These three stimuli proteome perturbations, which led increased abundance key antigen presentation pathways. TNF but not activated pathway, turn extensive dysregulation cytoskeletal adhesion proteins. In addition, several interferon-stimulated gene products. IL-1β similarly upregulated secretion chemokines, whereas only moderate increase IL-8, IFN-γ, secretion. Upregulation associated with type I IFN signaling observed co-cultured exposed LPS.The present study provides comprehensive both monoculture cells.

Language: Английский

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Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: June 23, 2020

Abstract SAMHD1 regulates cellular 2′-deoxynucleoside-5′-triphosphate (dNTP) homeostasis by catalysing the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate. In CD4 + myeloid lineage resting T-cells, blocks HIV-1 other viral infections depletion dNTP pool to a level that cannot support replication. mutations are associated with autoimmune disease Aicardi–Goutières syndrome hypermutated cancers. Furthermore, sensitises cancer cells nucleoside-analogue anti-cancer therapies is linked DNA repair suppression interferon response cytosolic nucleic acids. Nevertheless, despite its requirement in these processes, fundamental mechanism SAMHD1-catalysed remained unknown. Here, we present structural enzymological data showing utilises an active site, bi-metallic iron-magnesium centre positions hydroxide nucleophile in-line P α -O 5′ bond catalyse phosphoester hydrolysis. This precise molecular for catalysis, reveals how down-regulates modulates efficacy nucleoside-based anti-viral therapies.

Language: Английский

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