RT Journal Article
SR Electronic
T1 Nuclear Abl Drives Extracellular-Vesicle Transfer of miR-34c to Induce Bystander Effects of Radiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 209767
DO 10.1101/209767
A1 Shubhra Rastogi
A1 Amini Hwang
A1 Josolyn Chan
A1 Jean Y J Wang
YR 2017
UL http://biorxiv.org/content/early/2017/11/10/209767.abstract
AB Ionizing radiation (IR) activates DNA damage response (DDR) that includes induction of bystander effects (BE) in cells not directly targeted by radiation. How DDR pathways in irradiated cells stimulate BE in non-targeted cells is mostly unknown. We show here that extracellular vesicles from irradiated cells (EV-IR) induce reactive oxygen species (ROS), increase γH2AX and Rad51-foci, and reduce clonogenic survival when taken up by un-irradiated cells. Among the direct effects of IR is Abl nuclear accumulation; interestingly, EV-IR from Abl NLS-mutated cells could not induce BE, and restoration of nuclear Abl rescued that defect. Extending our previous finding that Abl stimulates miR-34c expression in DDR, we found that that nuclear Abl also increased miR-34c levels in EV-IR. Co-expression of miR-34c-minigene and activated Abl led to the production, without irradiation, EV-miR-34c with BE-inducing activity. Furthermore, EV-IR from miR34-knockout cells could not induce ROS and raised γH2AX levels to lesser extent than those from miR34-wild type cells. These results establish a novel role for nuclear Abl and miR-34c in transmitting DNA damage response from directly irradiated cells to un-irradiated bystander cells.