Targeting the DNA damage response and repair in cancer through nucleotide metabolism

Molecular Oncology, Journal Year: 2022, Volume and Issue: 16(21), P. 3792 - 3810

Published: May 18, 2022

The exploitation of the DNA damage response and repair proficiency cancer cells is an important anticancer strategy. replication are dependent upon supply deoxynucleoside triphosphate (dNTP) building blocks, which produced maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic lesions in cells. These same also activate antimetabolites, group chemotherapies that disrupt both metabolism Thus, dNTP enzymes targeted refine use chemotherapeutics, many remain standard care common cancers. In this review article, we will discuss approaches exemplified MTH1, MTHFD2 SAMHD1. © 2022 Authors. Molecular Oncology published John Wiley & Sons Ltd on behalf Federation European Biochemical Societies.

Language: Английский

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Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 220(1)

Published: Nov. 8, 2022

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon–driven inflammatory diseases. In these pathophysiological conditions, the DNA sensor cGAS and IFN production are linked damage. Physiological, tonic, signaling on other hand is essential functionally prime sensing pathways. Here, we show that low-level chronic damage mice lacking Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed a p53-deficient, not mismatch repair-deficient background. Increased did result higher levels interferon. Instead, found interferon response SAMHD1-deficient was driven by MDA5/MAVS pathway required functional priming through pathway. Our work positions upstream tonic Samhd1-deficient highlights an important role physiological innate immune priming.

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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Single-Stranded Nucleic Acids Bind to the Tetramer Interface of SAMHD1 and Prevent Formation of the Catalytic Homotetramer

Biochemistry, Journal Year: 2016, Volume and Issue: 55(44), P. 6087 - 6099

Published: Oct. 24, 2016

Sterile alpha motif and HD domain protein 1 (SAMHD1) is a unique enzyme that plays important roles in nucleic acid metabolism, viral restriction, the pathogenesis of autoimmune diseases cancer. Although much attention has been focused on its dNTP triphosphohydrolase activity restriction disease, SAMHD1 also binds to single-stranded RNA DNA. Here we utilize UV cross-linking method using 5-bromodeoxyuridine-substituted oligonucleotides coupled with high-resolution mass spectrometry identify binding site for acids (ssNAs) SAMHD1. Mapping cross-linked amino surface existing crystal structures demonstrated ssNA lies largely along dimer-dimer interface, sterically blocking formation homotetramer required dNTPase activity. Surprisingly, disordered C-terminus (residues 583-626) was implicated binding. An interaction between this region confirmed studies purified 583-626 peptide. Despite recent report possesses polyribonucleotide phosphorylase activity, did not detect any such presence inorganic phosphate, indicating unrelated proposed These data suggest an antagonistic regulatory mechanism which mutually exclusive oligomeric state requirements hydrolase modulate these two functions within cell.

Language: Английский

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