6brg

Structural highlights

Function

SAMH1_MOUSE 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 (By similarity). Has deoxynucleoside triphosphate (dNTPase) activity, which is required to restrict infection by viruses: 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 (PubMed:23972988, PubMed:23872947, PubMed:26667483, PubMed:31548683, PubMed:29379009). Likewise, suppresses LINE-1 retrotransposon activity (PubMed:26667483). In addition to virus restriction, dNTPase activity acts as a regulator of DNA precursor pools by regulating dNTP pools (By similarity). Phosphorylation at Thr-634 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 (By similarity). 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 (By similarity). 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 (By similarity). Ability to promote DNA end resection at stalled replication forks is independent of dNTPase activity (By similarity). Enhances immunoglobulin hypermutation in B-lymphocytes by promoting transversion mutation (PubMed:29669924).[UniProtKB:Q9Y3Z3]^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Rehwinkel J, Maelfait J, Bridgeman A, Rigby R, Hayward B, Liberatore RA, Bieniasz PD, Towers GJ, Moita LF, Crow YJ, Bonthron DT, Reis e Sousa C. SAMHD1-dependent retroviral control and escape in mice. EMBO J. 2013 Sep 11;32(18):2454-62. PMID:23872947 doi:10.1038/emboj.2013.163
2. ↑ Behrendt R, Schumann T, Gerbaulet A, Nguyen LA, Schubert N, Alexopoulou D, Berka U, Lienenklaus S, Peschke K, Gibbert K, Wittmann S, Lindemann D, Weiss S, Dahl A, Naumann R, Dittmer U, Kim B, Mueller W, Gramberg T, Roers A. Mouse SAMHD1 has antiretroviral activity and suppresses a spontaneous cell-intrinsic antiviral response. Cell Rep. 2013 Aug 29;4(4):689-96. PMID:23972988 doi:10.1016/j.celrep.2013.07.037
3. ↑ Wittmann S, Behrendt R, Eissmann K, Volkmann B, Thomas D, Ebert T, Cribier A, Benkirane M, Hornung V, Bouzas NF, Gramberg T. Phosphorylation of murine SAMHD1 regulates its antiretroviral activity. Retrovirology. 2015 Dec 15;12:103. PMID:26667483 doi:10.1186/s12977-015-0229-6
4. ↑ Buzovetsky O, Tang C, Knecht KM, Antonucci JM, Wu L, Ji X, Xiong Y. The SAM domain of mouse SAMHD1 is critical for its activation and regulation. Nat Commun. 2018 Jan 29;9(1):411. doi: 10.1038/s41467-017-02783-8. PMID:29379009 doi:http://dx.doi.org/10.1038/s41467-017-02783-8
5. ↑ Thientosapol ES, Bosnjak D, Durack T, Stevanovski I, van Geldermalsen M, Holst J, Jahan Z, Shepard C, Weninger W, Kim B, Brink R, Jolly CJ. SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation. Proc Natl Acad Sci U S A. 2018 May 8;115(19):4921-4926. PMID:29669924 doi:10.1073/pnas.1719771115
6. ↑ Deutschmann J, Schneider A, Gruska I, Vetter B, Thomas D, Kießling M, Wittmann S, Herrmann A, Schindler M, Milbradt J, Ferreirós N, Winkler TH, Wiebusch L, Gramberg T. A viral kinase counteracts in vivo restriction of murine cytomegalovirus by SAMHD1. Nat Microbiol. 2019 Dec;4(12):2273-2284. PMID:31548683 doi:10.1038/s41564-019-0529-z
7. ↑ Buzovetsky O, Tang C, Knecht KM, Antonucci JM, Wu L, Ji X, Xiong Y. The SAM domain of mouse SAMHD1 is critical for its activation and regulation. Nat Commun. 2018 Jan 29;9(1):411. doi: 10.1038/s41467-017-02783-8. PMID:29379009 doi:http://dx.doi.org/10.1038/s41467-017-02783-8