Deoxynucleoside triphosphate triphosphohydrolase SAMHD1

Definition:

Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks. Has deoxynucleoside triphosphate (dNTPase) activity, which is required to restrict infection by viruses, such as HIV-1: dNTPase activity reduces cellular dNTP levels to levels too low for retroviral reverse transcription to occur, blocking early-stage virus replication in dendritic and other myeloid cells. Likewise, suppresses LINE-1 retrotransposon activity. Not able to restrict infection by HIV-2 virus; because restriction activity is counteracted by HIV-2 viral protein Vpx. In addition to virus restriction, dNTPase activity acts as a regulator of DNA precursor pools by regulating dNTP pools. Phosphorylation at Thr-592 acts as a switch to control dNTPase-dependent and -independent functions: it inhibits dNTPase activity and ability to restrict infection by viruses, while it promotes DNA end resection at stalled replication forks. Functions during S phase at stalled DNA replication forks to promote the resection of gapped or reversed forks: acts by stimulating the exonuclease activity of MRE11, activating the ATR-CHK1 pathway and allowing the forks to restart replication. Its ability to promote degradation of nascent DNA at stalled replication forks is required to prevent induction of type I interferons, thereby preventing chronic inflammation. Ability to promote DNA end resection at stalled replication forks is independent of dNTPase activity. Enhances immunoglobulin hypermutation in B-lymphocytes by promoting transversion mutation (By similarity).

References:

[1]. Jeongmin Ryoo, et al. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med. 2014 Aug;20(8):936-41. [Content Brief]

[2]. Flavie Coquel, et al. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature. 2018 May;557(7703):57-61. [Content Brief]

[3]. Alexandra Herrmann, et al. The SAMHD1-mediated block of LINE-1 retroelements is regulated by phosphorylation. Mob DNA. 2018 Mar 28;9:11. [Content Brief]

[4]. Chenxiang Tang, et al. Impaired dNTPase activity of SAMHD1 by phosphomimetic mutation of Thr-592. J Biol Chem. 2015 Oct 30;290(44):26352-9. [Content Brief]

[5]. David Schwefel, et al. Structural basis of lentiviral subversion of a cellular protein degradation pathway. Nature. 2014 Jan 9;505(7482):234-8. [Content Brief]

[6]. Kasia Hrecka, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature. 2011 Jun 29;474(7353):658-61. [Content Brief]

[7]. David C Goldstone, et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature. 2011 Nov 6;480(7377):379-82. [Content Brief]

[8]. Waaqo Daddacha, et al. SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination. Cell Rep. 2017 Aug 22;20(8):1921-1935. [Content Brief]

[9]. Ke Zhao, et al. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1. Cell Rep. 2013 Sep 26;4(6):1108-15. [Content Brief]

[10]. Alexandra Cribier, et al. Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1. Cell Rep. 2013 Apr 25;3(4):1036-43. [Content Brief]

[11]. Laurence H Arnold, et al. Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction. PLoS Pathog. 2015 Oct 2;11(10):e1005194. [Content Brief]

[12]. Nadine Laguette, et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature. 2011 May 25;474(7353):654-7. [Content Brief]

[13]. Jonathan Maelfait, et al. Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1. Cell Rep. 2016 Aug 9;16(6):1492-1501. [Content Brief]

[14]. Chunfeng Zhu, et al. Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase. Nat Commun. 2013;4:2722. [Content Brief]

[15]. Gillian I Rice, et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009 Jul;41(7):829-32. [Content Brief]

[16]. Kyle J Seamon, et al. SAMHD1 is a single-stranded nucleic acid binding protein with no active site-associated nuclease activity. Nucleic Acids Res. 2015 Jul 27;43(13):6486-99. [Content Brief]

[17]. Natalia Beloglazova, et al. Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutieres syndrome and HIV-1 restriction. J Biol Chem. 2013 Mar 22;288(12):8101-8110. [Content Brief]

[18]. Elisa Franzolin, et al. The deoxynucleotide triphosphohydrolase SAMHD1 is a major regulator of DNA precursor pools in mammalian cells. Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14272-7. [Content Brief]

[19]. Tommy E White, et al. The retroviral restriction ability of SAMHD1, but not its deoxynucleotide triphosphohydrolase activity, is regulated by phosphorylation. Cell Host Microbe. 2013 Apr 17;13(4):441-51. [Content Brief]

[20]. Tommy E White, et al. A SAMHD1 mutation associated with Aicardi-Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans. Hum Mutat. 2017 Jun;38(6):658-668. [Content Brief]

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