DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3.
The response to DNA damage, which regulates nuclear processes such as DNA repair, transcription, and cell cycle, has been studied thoroughly. However, the cytoplasmic response to DNA damage is poorly understood. Here, we demonstrate that DNA damage triggers dramatic reorganization of the Golgi, resulting in its dispersal throughout the cytoplasm. We further show that DNA-damage-induced Golgi dispersal requires GOLPH3/MYO18A/F-actin and the DNA damage protein kinase, DNA-PK. In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents. Identification of the DNA-damage-induced Golgi response reveals an unexpected pathway through DNA-PK, GOLPH3, and MYO18A that regulates cell survival following DNA damage.
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
Suzette E
SE
Farber-Katz
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
Holly C
HC
Dippold
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
Matthew D
MD
Buschman
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
Marshall C
MC
Peterman
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
Mengke
M
Xing
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
Christopher J
CJ
Noakes
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
John
J
Tat
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
Michelle M
MM
Ng
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
Juliati
J
Rahajeng
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA.
David M
DM
Cowan
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0653, USA.
Greg J
GJ
Fuchs
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0653, USA.
Huilin
H
Zhou
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0707, USA. Electronic address: sjfield@ucsd.edu.
Seth J
SJ
Field
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009218:Myosins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D016415:Sequence Alignment
D051747:DNA-Activated Protein Kinase; D008565:Membrane Proteins; D009218:Myosins; C429024:GOLPH3 protein, human; C407152:MYO18A protein, human