DNA-PK- and GOLPH3-dependent Golgi dispersal is required for cell survival after DNA damage.
Major finding: DNA-PK- and GOLPH3-dependent Golgi dispersal is required for cell survival after DNA damage.
Mechanism: GOLPH3 phosphorylation by DNA-PK promotes binding to the unconventional myosin MYO18A.
Impact: Overexpression of GOLPH3 in human cancers may promote chemoresistance.
DNA damage activates an array of nuclear responses, but cytoplasmic responses to DNA damage and their biologic implications have not been extensively studied. Farber-Katz and colleagues found that diverse DNA damaging agents induced the dispersal of the Golgi throughout the cytoplasm in many cell types, a phenomenon that was unrelated to apoptosis or cell-cycle arrest and persisted long after cells recovered. The Golgi membrane protein GOLPH3, which regulates Golgi morphology by linking trans-Golgi membranes to the actin cytoskeleton through its interaction with the unconventional myosin MYO18A, was required for DNA damage–induced Golgi dispersal. Moreover, the DNA damage–activated protein kinase DNA-PK was specifically required for Golgi dispersal after DNA damage and increased its affinity for MYO18A by directly phosphorylating GOLPH3 on two conserved sites. Consistent with these findings, unphosphorylatable mutants of GOLPH3 failed to rescue DNA damage–induced Golgi dispersal in cells lacking endogenous GOLPH3, implicating direct signaling from DNA-PK to GOLPH3 in the regulation of this process. DNA damage also induced the accumulation of a reporter protein at the Golgi, raising the possibility that Golgi dispersal results in impaired trafficking of proteins from the Golgi to the plasma membrane. Of note, knockdown of DNA-PK, GOLPH3, or MYO18A caused an increase in apoptosis following treatment with DNA-damaging agents, whereas overexpression of GOLPH3, which frequently occurs in human cancers and is correlated with a poor prognosis, conferred a survival advantage that was dependent on both its localization to the Golgi and phosphorylation by DNA-PK. Although further investigation of the mechanism by which impaired protein trafficking confers cellular protection is warranted, these findings identify an important role for the DNA-PK−GOLPH3−MYO18A pathway in regulating Golgi dispersal and cell survival following DNA damage and raise the possibility that GOLPH3 expression may be predictive of responsiveness to chemotherapy.
Farber-Katz SE, Dippold HC, Buschman MD, Peterman MC, Xing M, Noakes CJ, et al. DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3. Cell 2014;156:413–27.
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