How DNA Damage Impacts Golgi

E-mail Print PDF



In studying the affect of DNA damage on the Golgi, the cell's shipping department, a research team from the University of California, San Diego School of Medicine and the Ludwig Institute for Cancer Research have found a new pathway initiated by DNA damage, with significant costs for the body's cellular response to chemotherapy.

Standard cancer treatments, including numerous chemotherapy drugs and radiation therapy, act on cells by causing DNA damage. In various cancer cells, DNA damage activiates signaling pathways that can ultimately lead to cell death, the foundation of the use of these treatments for cancer.

A better understanding of the signaling pathways that are turned on in cells in reaction to DNA damage, and the impact they exercise to determine the fate of the cell to live or die, eventually could result in a more effective use of these DNA damaging agents to treat cancer.

A study published in the journal Cell , headed by associate professor of medicine at UC San Diego School of Medicine, Seth Field, MD, PhD, displays that DNA damage triggers drastic reorganization of the Golgi. The Golgi operates as the cell's processing center for the delivery of proteins, lipids, and other large molecules to their final destinations outside of the cell. The researchers demonstarted that, in mammalian cells, DNA damage causes the Golgi to split and scatter throughout the cell.

In 2009, the research team had discovered a three-way interaction between a particular Golgi protein, GOLPH3, a lipid signaling molecule, PtdIns(4)P and a contractile protein, MYO18A. The connection between the three applies a tensile force needed for effective formation of the tubules and vesicles necessary for extracellular transportation.

Later screening distinguished GOLPH3 as an oncogene overexpressed in many human cancers, which can transform cells into tumorous cells. This study reveals that common cancer therapeutic agents, by triggering DNA damage, activate GOLPH3.

Studying the mechanism of Golgi dispersal, the researchers found that Golgi dispersal in response to DNA damage involves a new signaling pathway that directly links the DNA damage response to the Golgi.

The study also revelaed that the DNA damage-activated protein kinase, DNA-PK, directly modifies the Golgi protein GOLPH3 by phosphorylation on a specific site. This, in turn, enhances the interaction of GOLPH3 with MYO18A, increasing the tensile force applied to the Golgi, causing Golgi dispersal.

Meddling with Golgi dispersal following DNA damage by depletion of any of the factors of this pathway, including DNA-PK, GOLPH3, or MYO18A , resulted in enhanced cell killing by DNA damaging agents. The researchers determined that this pathway is normally required to allow cells to survive DNA damage.

"We further found that overexpression of GOLPH3, as is seen in human cancers, protects cells from killing by DNA damaging agents," said Field.

"Identification of such a Golgi response reveals an unexpected pathway through DNA-PK, GOLPH3 and MYO18A that regulates cell survival following DNA damage. This unappreciated feature of the cellular DNA damage response plays a significant role in determining cell survival," he added.

These signals are relayed buying clomid online safe which then is by a number of such as medial preoptic and paraventricular nulcei.