title: Beclin 1 and UVRAG confer protection from radiation-induced DNA damage and maintain centrosome stability in colorectal cancer cells.
abstract: Beclin 1 interacts with UV-irradiation-resistance-associated gene (UVRAG) to form core complexes that induce autophagy. While cells with defective autophagy are prone to genomic instability that contributes to tumorigenesis, it is unknown whether Beclin1 or UVRAG can regulate the DNA damage/repair response to cancer treatment in established tumor cells. We found that siRNA knockdown of Beclin 1 or UVRAG can increase radiation-induced DNA double strand breaks (DSBs), shown by pATM and γH2Ax, and promote colorectal cancer cell death. Furthermore, knockdown of Beclin 1, UVRAG or ATG5 increased the percentage of irradiated cells with nuclear foci expressing 53BP1, a marker of nonhomologous end joining but not RAD51 (homologous recombination), compared to control siRNA. Beclin 1 siRNA was shown to attenuate UVRAG expression. Cells with a UVRAG deletion mutant defective in Beclin 1 binding showed increased radiation-induced DSBs and cell death compared to cells with ectopic wild-type UVRAG. Knockdown of Beclin 1 or UVRAG, but not ATG5, resulted in a significant increase in centrosome number (γ-tubulin staining) in irradiated cells compared to control siRNA. Taken together, these data indicate that Beclin 1 and UVRAG confer protection against radiation-induced DNA DSBs and may maintain centrosome stability in established tumor cells.
authors: Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America.
authors: Jae Myung
authors: JM
authors: Park
authors: Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America.
authors: David
authors: D
authors: Tougeron
authors: Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America.
authors: Shengbing
authors: S
authors: Huang
authors: Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America.
authors: Koichi
authors: K
authors: Okamoto
authors: Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America.
authors: Frank A
authors: FA
authors: Sinicrope
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D019610:Cytoprotection / Q000187:drug effects / Q000528:radiation effects*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D005472:Fluorouracil / Q000494:pharmacology; D005720:Gamma Rays; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000528:radiation effects; D051135:Rad51 Recombinase / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C498301:TP53BP1 protein, human; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C408122:UVRAG protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D005472:Fluorouracil