RNaseH2 mutants that cause Aicardi-Goutieres syndrome are active nucleases.
Mutations in the genes encoding the RNaseH2 and TREX1 nucleases have been identified in patients with Aicardi-Goutieres syndrome (AGS). To determine if the AGS RNaseH2 mutations result in the loss of nuclease activity, the human wild-type RNaseH2 and four mutant complexes that constitute the majority of mutations identified in AGS patients have been prepared and tested for ribonuclease H activity. The heterotrimeric structures of the mutant RNaseH2 complexes are intact. Furthermore, the ribonuclease H activities of the mutant complexes are indistinguishable from the wild-type enzyme with the exception of the RNaseH2 subunit A (Gly37Ser) mutant, which exhibits some evidence of altered nuclease specificity. These data indicate that the mechanism of RNaseH2 dysfunction in AGS cannot be simply explained by loss of ribonuclease H activity and points to a more complex mechanism perhaps mediated through altered interactions with as yet identified nucleic acids or protein partners.
Perrino
Fred W
FW
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA. fperrino@wfubmc.edu
Harvey
Scott
S
Shaban
Nadine M
NM
Hollis
Thomas
T
D019943:Amino Acid Substitution; D020739:Brain Diseases, Metabolic, Inborn / Q000201:enzymology* / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D020836:Protein Structure, Quaternary / Q000235:genetics; D016914:Ribonuclease H / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome
C091139:ribonuclease HII; D016914:Ribonuclease H