title: A novel radioprotective function for the mitochondrial tumor suppressor protein Fus1.
abstract: FUS1/TUSC2 is a mitochondrial tumor suppressor with activity to regulate cellular oxidative stress by maintaining balanced ROS production and mitochondrial homeostasis. Fus1 expression is inhibited by ROS, suggesting that individuals with a high level of ROS may have lower Fus1 in normal tissues and, thus, may be more prone to oxidative stress-induced side effects of cancer treatment, including radiotherapy. As the role of Fus1 in the modulation of cellular radiosensitivity is unknown, we set out to determine molecular mechanisms of Fus1 involvement in the IR response in normal tissues. Mouse whole-body irradiation methodology was employed to determine the role for Fus1 in the radiation response and explore underlying molecular mechanisms. Fus1(-/-) mice were more susceptible to radiation compared with Fus1(+/+) mice, exhibiting increased mortality and accelerated apoptosis of the GI crypt epithelial cells. Following untimely reentrance into the cell cycle, the Fus1(-/-) GI crypt cells died at accelerated rate via mitotic catastrophe that resulted in diminished and/or delayed crypt regeneration after irradiation. At the molecular level, dysregulated dynamics of activation of main IR response proteins (p53, NFκB, and GSK-3β), as well as key signaling pathways involved in oxidative stress response (SOD2, PRDX1, and cytochrome c), apoptosis (BAX and PARP1), cell cycle (Cyclins B1 and D1), and DNA repair (γH2AX) were found in Fus1(-/-) cells after irradiation. Increased radiosensitivity of other tissues, such as immune cells and hair follicles was also detected in Fus1(-/-) mice. Our findings demonstrate a previously unknown radioprotective function of the mitochondrial tumor suppressor Fus1 in normal tissues and suggest new individualized therapeutic approaches based on Fus1 expression.
authors.affiliation: Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Yazlovitskaya
authors.forename: R
authors.initials: R
authors.lastname: Uzhachenko
authors.forename: P A
authors.initials: PA
authors.lastname: Voziyan
authors.forename: W G
authors.initials: WG
authors.lastname: Yarbrough
authors.forename: A V
authors.initials: AV
authors.lastname: Ivanova
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D011833:Radiation Injuries, Experimental; D011836:Radiation Tolerance; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014916:Whole-Body Irradiation
chemical_list: D025521:Tumor Suppressor Proteins; C543627:Tusc2 protein, mouse