title: Deubiquitinase OTUD5 mediates the sequential activation of PDCD5 and p53 in response to genotoxic stress.
abstract: Programmed cell death 5 (PDCD5) positively regulates p53-mediated apoptosis and rapidly accumulates upon DNA damage. However, the underlying mechanism of PDCD5 upregulation during the DNA damage response remains unknown. Here, we found that OTU deubiquitinase 5 (OTUD5) was bound to PDCD5 in response to etoposide treatment and increased the stability of PDCD5 by mediating deubiquitination of PDCD5 at Lys-97/98. Overexpression of OTUD5 efficiently enhanced the activation of both PDCD5 and p53. Conversely, PDCD5 knockdown greatly attenuated the effect of OTUD5 on p53 activation. In addition, when OTUD5 was depleted, PDCD5 failed to facilitate p53 activation, demonstrating an essential role for the PDCD5-OTUD5 network in p53 activation. Importantly, we found that OTUD5-dependent PDCD5 stabilization was required for sequential activation of p53 in response to genotoxic stress. The sequential activation of PDCD5 and p53 was abrogated by knockdown of OTUD5. Finally, impairment of the genotoxic stress response upon PDCD5 ablation was substantially rescued by reintroducing PDCD5(WT) but not PDCD5(E94D) (defective for OTUD5 interaction) or PDCD5(E16D) (defective for p53 interaction). Together, our findings have uncovered an apoptotic signaling cascade linking PDCD5, OTUD5, and p53 during genotoxic stress responses.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyo-Kyoung
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Fertility Center of CHA General Hospital, CHA Research Institute, CHA University, Seoul, Korea.
authors.forename: Youngsok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences and Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Sungmin
authors.initials: S
authors.lastname: Kwak
authors.affiliation: Department of Biomedical Sciences and Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Korea. Electronic address: choikc75@amc.seoul.kr.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; C117283:PDCD5 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D010450:Endopeptidases; C525076:OTUD5 protein, human
keywords: Cell death; Genotoxic stress response; OTUD5; PDCD5; p53