SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

Cell Reports, Journal Year: 2017, Volume and Issue: 20(8), P. 1921 - 1935

Published: Aug. 1, 2017

Highlights•SAMHD1 deficiency or Vpx-mediated degradation sensitizes cells to DSB-inducing agents•SAMHD1 localizes DNA double-strand breaks in response damage•SAMHD1 promotes HR and end resection independent of its dNTPase activity•SAMHD1 complexes with CtIP facilitates recruitment damage sitesSummaryDNA break (DSB) repair by homologous recombination (HR) is initiated CtIP/MRN-mediated maintain genome integrity. SAMHD1 a dNTP triphosphohydrolase, which restricts HIV-1 infection, mutations are associated Aicardi-Goutières syndrome cancer. We show that has dNTPase-independent function promoting facilitate DSB HR. causes hypersensitivity agents, recruited DSBs. via conserved C-terminal domain recruits DSBs Significantly, cancer-associated mutant impaired interaction, but not dNTPase-inactive SAMHD1, fails rescue the impairment depletion. Our findings define for HR-mediated facilitating accrual promote resection, providing insight into how integrity.Graphical abstract

Language: Английский

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Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: June 4, 2018

Abstract SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity regulated by T592 phosphorylation. Here, we show that dephosphorylation at controlled during the cell cycle, occurring M/G 1 transition proliferating cells. Using several complementary proteomics biochemical approaches, identify phosphatase PP2A-B55α responsible rendering antivirally active. specifically targeted holoenzymes mitotic exit, line with observations key exit mammalian Strikingly, as HeLa or activated primary CD4 + T enter G phase, pronounced reduction of RT products observed upon infection dependent on presence dephosphorylated SAMHD1. Moreover, PP2A controls pT592 level monocyte-derived macrophages (MDMs). Thus, holoenzyme regulator to switch

Language: Английский

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Dendritic Cells, the Double Agent in the War Against HIV-1

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Oct. 23, 2019

Human Immunodeficiency Virus (HIV) infects cells from the immune system and has thus developed tools to circumvent host immunity use it in its advance. Dendritic (DCs) are first encounter HIV, being main antigen (Ag) presenting cells, they link innate adaptive responses. While DCs work promote an efficient response halt infection, HIV-1 ways take advantage of their role uses gain faster more access CD4+ T cells. Due ability activate a specific response, promising candidates achieve functional cure but knowing molecular partakers that determine relationship between virus cell is key for rational successful design DC-based therapy. In this review, we summarize current state knowledge on how both DC subsets (myeloid plasmacytoid DCs) act presence HIV-1, focus different pathways can after binding DC. First, explore consequences recognition by each receptor DCs, including CD4 DC-SIGN. Second, look at cellular mechanisms prevent productive infection weapons turn defense into Trojan horse hides all way cell. Finally, discuss possible outcomes DC-T contact.

Language: Английский

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Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Aug. 2, 2019

Abstract Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms action remain incompletely understood, predictive biomarkers for HMA efficacy lacking. Here, we show that bioactive metabolite triphosphate, but not functions activator substrate triphosphohydrolase SAMHD1 is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis bone marrow specimens from AML patients at diagnosis revealed expression leukemic cells inversely correlates with clinical response decitabine, azacytidine. ablation increases antileukemic activity cell lines, primary blasts, xenograft models. acquire resistance partly by up-regulation. Together, our data suggest a biomarker stratified use hypomethylating potential target decitabine-resistant leukemia.

Language: Английский

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SAMHD1 Suppression of Antiviral Immune Responses

Trends in Microbiology, Journal Year: 2018, Volume and Issue: 27(3), P. 254 - 267

Published: Oct. 15, 2018

Language: Английский

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Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 2, 2021

Abstract SAMHD1 impedes infection of myeloid cells and resting T lymphocytes by retroviruses, the enzymatic activity protein—dephosphorylation deoxynucleotide triphosphates (dNTPs)—implicates dNTP depletion in innate antiviral immunity. Here we show that allosteric binding sites enzyme are plastic can accommodate oligonucleotides place activators, GTP dNTP. displays a preference for containing phosphorothioate bonds Rp configuration located 3’ to G nucleotides (GpsN), modification pattern occurs mechanism defense prokaryotes. In presence dNTPs, GpsN-containing promotes formation distinct tetramer with mixed occupancy sites. Mutations impair mixed-occupancy complex abolish antiretroviral SAMHD1, but not its ability deplete dNTPs. The findings link nucleic acid shed light on immunomodulatory effects synthetic phosphorothioated raise questions about role phosphorothioation human

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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Post-translational Modification-Based Regulation of HIV Replication

Frontiers in Microbiology, Journal Year: 2018, Volume and Issue: 9

Published: Sept. 11, 2018

Human immunodeficiency virus (HIV) relies heavily on the host cellular machinery for production of viral progeny. To exploit proteins replication and to overcome factors with antiviral activity, HIV has evolved a set regulatory accessory shape an optimized environment its facilitate evasion from immune system. Several pathways are hijacked by modulate critical steps during life cycle. Thereby, post-translational modifications (PTMs) gain increasingly attention as modifying enzymes regulate virtually every step This review summarizes current knowledge HIV-host interactions influenced PTMs special focus acetylation, ubiquitination, phosphorylation linked signaling replication. Insights into these surmised aid development new intervention strategies.

Language: Английский

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SAMHD1 in cancer: curse or cure?

Journal of Molecular Medicine, Journal Year: 2021, Volume and Issue: 100(3), P. 351 - 372

Published: Sept. 4, 2021

Abstract Human sterile α motif and HD domain-containing protein 1 (SAMHD1), originally described as the major cellular deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) balancing intracellular deoxynucleotide (dNTP) pool, has come recently into focus of cancer research. As outlined in this review, SAMHD1 been reported to be mutated a variety types expression is dysregulated many cancers. Therefore, regarded tumor suppressor certain tumors. Moreover, it proposed that might fulfill requirements driver gene development or promote so-called mutator phenotype. Besides its role dNTPase, several novel functions have light only recently, including negative regulator innate immune responses facilitator DNA end resection during replication repair. can placed at crossroads various processes. The present review summarizes chemotherapy sensitivity, highlights mutations found types, aims discuss functional consequences well underlying mechanisms dysregulation potentially involved development.

Language: Английский

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