Li, M. Z. | Search bioRxiv

bioRxiv2024

Identification of MYC synthetic lethal genes and networks

MYC is a potent oncogene that is frequently overexpressed in human tumors arising in different tissues. To date there are no approved therapies to directly antagonize oncogenic MYC and its role in driving tumorigenesis. As an alternative approach we employed genetic screens using CRISPR and shRNA to identify the genes that are required for the survival and growth of cells harboring high levels of MYC expression. We find that cells with elevated MYC require the expression of many pro-growth and metabolic pathways including genes involved in mitochondrial citrate production and transport. This citrate producing pathway is critical for cells with elevated MYC to generate the necessary acetyl-CoA to drive the lipid synthesis required for increased proliferation. Inhibition of this pathway results in reduced proliferation and in vivo tumor growth providing a potential therapeutic strategy to target MYC-driven cancers. HIGHLIGHTS- CRISPR and shRNA screens identify synthetic lethal interactions with overexpressed MYC - MYC overexpressing cells are more sensitive to disruption of citrate production and transport - Inhibition of SLC25A1 reduces growth of MYC driven tumors

cancer biology↗

bioRxiv2021

Horizontal Transfer of Histone H3 by Mammalian Cells

The authors have withdrawn their manuscript because many of the experiments described in this paper have not been reproducible, or at least are not robust, in the hands of other members of the Kaelin Laboratory who were not initially involved in this work. While we do see apparent secretion of histone H3 under some conditions, it is usually accompanied by secretion of histone H4. In this regard, the Halo tagged-histone H3 and Halo-tagged H4 constructs used for the single molecule imaging studies we reported, which seemingly confirmed specific secretion and transfer of histone H3, were purported to be sequence validated. Upon resequencing these constructs we discovered a non-synonymous mutation in the Halo tag of the H4 construct. We then redid the imaging experiments with the corrected Halo-H4 together with Halo-H3 and, in contrast to our earlier study, unfused Halo. These experiments were difficult to interpret because of the background signal seen with the unfused Halo but did not support specific secretion and transfer of histones (let alone specific secretion and transfer of histone H3). We have, in some experiments, observed transfer of H3-Cre into reporter cells ex vivo and in vivo, but 1) the transfer is not specific for H3-Cre versus H4-Cre, 2) the transfer efficiency is highly variable, and 3) the transfer efficiency is typically much less than reported in our original paper. We do not yet know whether this lack of reproducibility and robustness reflects technical and biological variables that we do not yet understand and hence were not captured in our experimental protocols. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

cell biology↗