Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3

• DOI: 10.1016/j.celrep.2018.01.076
• Publication Date: 2018-02-23T15:43:50Z
• Authors: Karina N. Gonzale...; Elma Zaganjor; Yoshinori Ishikawa; Jessica B. Spinelli; Haejin Yoon; Jia-Ren Lin; F. Kyle Satterstrom; Alison Ringel; Stacy Mulei; Amanda Souza; Joshua M. Gorham; Craig C. Benson; Jonathan G. Seidman; Peter K. Sorger; Clary B. Clish; Marcia C. Haigis
• Keywords: SIRT3; KLF4

Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer neurodegeneration high-fat diet (HFD)-induced metabolic disorders. Here, we performed small-molecule screen identified an unexpected vulnerability associated with SIRT3 loss. Azaserine, glutamine analog, was the top compound that inhibited growth proliferation of cells lacking SIRT3. Using stable isotope tracing glutamine, observed its increased incorporation into de novo nucleotide synthesis knockout (KO) cells. Furthermore, found KO upregulated diversion through hyperactive mTORC1 signaling. Overexpression suppressed vivo xenograft tumor model breast cancer. Thus, have uncovered loss by using unbiased screen.