title: The downregulation of the RNA-binding protein Staufen2 in response to DNA damage promotes apoptosis.
abstract: Staufen2 (Stau2) is an RNA-binding protein involved in cell fate decision by controlling several facets of mRNA processing including localization, splicing, translation and stability. Herein we report that exposure to DNA-damaging agents that generate replicative stress such as camptothecin (CPT), 5-fluoro-uracil (5FU) and ultraviolet radiation (UVC) causes downregulation of Stau2 in HCT116 colorectal cancer cells. In contrast, other agents such as doxorubicin and ionizing radiation had no effect on Stau2 expression. Consistently, Stau2 expression is regulated by the ataxia telangiectasia and Rad3-related (ATR) signaling pathway but not by the DNA-PK or ataxia telangiectasia mutated/checkpoint kinase 2 pathways. Stau2 downregulation is initiated at the level of transcription, independently of apoptosis induction. Promoter analysis identified a short 198 bp region which is necessary and sufficient for both basal and CPT-regulated Stau2 expression. The E2F1 transcription factor regulates Stau2 in untreated cells, an effect that is abolished by CPT treatment due to E2F1 displacement from the promoter. Strikingly, Stau2 downregulation enhances levels of DNA damage and promotes apoptosis in CPT-treated cells. Taken together our results suggest that Stau2 is an anti-apoptotic protein that could be involved in DNA replication and/or maintenance of genome integrity and that its expression is regulated by E2F1 via the ATR signaling pathway.
authors: Département de Biochimie et médecine moléculaire, Faculté de médecine, Université de Montréal, 2900 Edouard Montpetit Montréal, QC H3T 1J4, Canada.
authors: Xin
authors: X
authors: Zhang
authors: Département de Biochimie et médecine moléculaire, Faculté de médecine, Université de Montréal, 2900 Edouard Montpetit Montréal, QC H3T 1J4, Canada.
authors: Véronique
authors: V
authors: Trépanier
authors: Département de Biochimie et médecine moléculaire, Faculté de médecine, Université de Montréal, 2900 Edouard Montpetit Montréal, QC H3T 1J4, Canada.
authors: Remy
authors: R
authors: Beaujois
authors: Département de Biochimie et médecine moléculaire, Faculté de médecine, Université de Montréal, 2900 Edouard Montpetit Montréal, QC H3T 1J4, Canada.
authors: Wildriss
authors: W
authors: Viranaicken
authors: Département de Médecine, Université de Montréal and Centre de Recherche, Hôpital Maisonneuve Rosemont, Montréal, Québec, H1T 2M4, Canada.
authors: Elliot
authors: E
authors: Drobetsky
authors: Département de Biochimie et médecine moléculaire, Faculté de médecine, Université de Montréal, 2900 Edouard Montpetit Montréal, QC H3T 1J4, Canada luc.desgroseillers@umontreal.ca.
authors: Luc
authors: L
authors: DesGroseillers
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D002461:Cell Line, Transformed; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D009153:Mutagens / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D003598:Cytoskeletal Proteins; D050687:E2F1 Transcription Factor; D009153:Mutagens; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C492185:STAU1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002166:Camptothecin