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SAMHD1 is a nucleic‐acid binding protein that is mislocalized due to aicardi–goutières syndrome‐associated mutations
Author(s) -
Goncalves Adriana,
Karayel Evren,
Rice Gillian I,
Bennett Keiryn L,
Crow Yanick J,
SupertiFurga Giulio,
Bürckstümmer Tilmann
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22087
Subject(s) - samhd1 , biology , nuclease , rnase h , rnase p , nucleic acid , exonuclease , mutant , microbiology and biotechnology , dna , rna , gene , biochemistry , polymerase , reverse transcriptase
Aicardi–Goutières syndrome (AGS) is a rare inherited autoimmune disease caused by mutations in genes encoding the RNase H2 subunits A, B, and C; the DNase three prime repair exonuclease 1 (TREX1); and sterile alpha motif (SAM) domain and HD domain‐containing protein 1 (SAMHD1). Using unbiased affinity purification coupled to protein mass spectrometry, we identify SAMHD1 as a nucleic‐acid‐binding protein displaying a preference for RNA over DNA. In contrast to TREX1 and the RNase H2 complex, SAMHD1 has no obvious nuclease activity. In addition, interrogating truncation mutants of SAMHD1 observed in AGS patients, we map the nucleic‐acid‐binding domain to residues 164–442, thus overlapping with the HD domain. Furthermore, we show that although wild‐type SAMHD1 displays almost exclusive nuclear localization, 11 of 12 SAMHD1 mutants show at least partial mislocalization to the cytosol. Overall, these data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease. Hum Mutat 33:1116–1122, 2012. © 2012 Wiley Periodicals, Inc.