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From Proteopedia
SAMHD1 HD domain bound to decitabine triphosphate
Structural highlights
DiseaseSAMH1_HUMAN Defects in SAMHD1 are the cause of Aicardi-Goutieres syndrome type 5 (AGS5) [MIM:612952. A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.[1] [2] Defects in SAMHD1 are the cause of chilblain lupus type 2 (CHBL2) [MIM:614415. A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade.[3] FunctionSAMH1_HUMAN Putative nuclease involved in innate immune response by acting as a negative regulator of the cell-intrinsic antiviral response. May play a role in mediating proinflammatory responses to TNF-alpha signaling.[4] [5] Publication Abstract from PubMedHypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia. Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML.,Oellerich T, Schneider C, Thomas D, Knecht KM, Buzovetsky O, Kaderali L, Schliemann C, Bohnenberger H, Angenendt L, Hartmann W, Wardelmann E, Rothenburger T, Mohr S, Scheich S, Comoglio F, Wilke A, Strobel P, Serve H, Michaelis M, Ferreiros N, Geisslinger G, Xiong Y, Keppler OT, Cinatl J Jr Nat Commun. 2019 Aug 2;10(1):3475. doi: 10.1038/s41467-019-11413-4. PMID:31375673[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Angenendt L | Bohnenberger H | Buzovetsky O | Cinatl J | Comoglio F | Ferreiros N | Geisslinger G | Hartmann W | Kaderali L | Keppler OT | Knecht KM | Michaelis M | Mohr S | Oellerich T | Rothenburger T | Scheich S | Schliemann C | Schneider C | Serve H | Strobel P | Thomas D | Wardelmann E | Wilke A | Xiong Y
