Abstract
BackgroundCells respond to DNA damage by activating the phosphatidylinositol-3 kinase-related kinases, p53 and other pathways to promote cell cycle arrest, apoptosis, and/or DNA repair. Here we report that protein palmitoylation, a modification carried out by protein acyltransferases with zinc-finger and Asp-His-His-Cys domains (zDHHC), is required for proper DNA damage responses.ResultsInhibition of protein palmitoylation compromised DNA damage-induced activation of Atm, induction and activation of p53, cell cycle arrest at G2/M phase, and DNA damage foci assembly/disassembly in primary mouse embryonic fibroblasts. Furthermore, knockout of zDHHC16, a palmitoyltransferase gene identified as an interacting protein for c-Abl, a non-receptor tyrosine kinase involved in DNA damage response, reproduced most of the defects in DNA damage responses produced by the inhibition of protein palmitoylation.ConclusionsOur results revealed critical roles for protein palmitoylation and palmitoyltransferase zDHHC16 in early stages of DNA damage responses and in the regulation of Atm activation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12867-016-0065-9) contains supplementary material, which is available to authorized users.
Highlights
Cells respond to DNA damage by activating the phosphatidylinositol-3 kinase-related kinases, p53 and other pathways to promote cell cycle arrest, apoptosis, and/or DNA repair
Most of the zinc-finger and Asp-His-His-Cys domains (zDHHC) genes are expressed in mouse embryonic fibroblast (MEF) We chose to use primary MEFs for this study as most of the immortal cell lines show disrupted DNA damage response [18]
We first wanted to document which of the 23 protein-coding zDHHC genes were expressed in MEFs and whether their expression was altered by DNA damage
Summary
Cells respond to DNA damage by activating the phosphatidylinositol-3 kinase-related kinases, p53 and other pathways to promote cell cycle arrest, apoptosis, and/or DNA repair. We report that protein palmitoyla‐ tion, a modification carried out by protein acyltransferases with zinc-finger and Asp-His-His-Cys domains (zDHHC), is required for proper DNA damage responses. Protein S-acylation, is a posttranslational modification that adds a palmitate moiety to specific Cys residues by a family of proteins named protein acyltransferases (PATs) [1,2,3,4]. All PAT proteins contain a DHHC domain, a 51-amino acid Cys-rich domain with a highly conserved Asp-His-His-Cys sequence. The other regions of the PATs are variable. Unlike N-myristoylation or C-prenylation, S-acylation can be reversed by protein palmitoyl thioesterases and acyl protein thioesterases, making it a reversible lipid modification [5]. A number of cellular proteins have been reported to be palmitoylated, which are involved in different cellular
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