Mammalian
SIRT7 is a member of the sirtuin family that regulates multiple biological
processes including genome stability, metabolic pathways, stress responses,
and tumorigenesis. SIRT7 has been shown to be important for ribosome
biogenesis and transcriptional regulation. SIRT7 knockout mice exhibit
complications associated with fatty liver and increased aging in hematopoietic
stem cells. However, the molecular basis for its biological function
remains unclear, in part due to the lack of efficient enzymatic activity <i>in vitro</i>. Previously, we have demonstrated that double-stranded
DNA could activate SIRT7’s deacetylase activity <i>in
vitro</i>, allowing it to deacetylate H3K18 in the context of
chromatin. Here, we show that RNA can increase the catalytic efficiency
of SIRT7 even better and that SIRT7 can remove long chain fatty acyl
groups more efficiently than removing acetyl groups. Truncation and
mutagenesis studies revealed residues at both the amino and carboxyl
termini of SIRT7 that are involved in RNA-binding and important for
activity. RNA immunoprecipitation-sequencing (RIP-seq) identified
ribosomal RNA (rRNA) as the predominant RNA binding partner of SIRT7. The associated
RNA was able to effectively activate the deacetylase and defatty-acylase
activities of SIRT7. Knockdown of SIRT7 increased the lysine fatty
acylation of several nuclear proteins based on metabolic labeling
with an alkyne-tagged fatty acid analog, supporting that the defatty-acylase
activity of SIRT7 is physiologically relevant. These findings provide
important insights into the biological functions of SIRT7, as well
as an improved platform to develop SIRT7 modulators
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