title: YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5.
abstract: Programmed cell death 5 (PDCD5) plays a crucial role in TP53-mediated apoptosis, but the regulatory mechanism of PDCD5 itself during apoptosis remains obscure. We identified YY1-associated factor 2 (YAF2) as a novel PDCD5-interacting protein in a yeast two-hybrid screen for PDCD5-interacting proteins. We found that YY1-associated factor 2 (YAF2) binds to and increases PDCD5 stability by inhibiting the ubiquitin-dependent proteosomal degradation pathway. However, knocking-down of YAF2 diminishes the levels of PDCD5 protein but not the levels of PDCD5 mRNA. Upon genotoxic stress response, YAF2 promotes TP53 activation via association with PDCD5. Strikingly, YAF2 failed to promote TP53 activation in the deletion of PDCD5, whereas restoration of wild-type PDCD5WT efficiently reversed the ineffectiveness of YAF2 on TP53 activation. Conversely, PDCD5 efficiently overcame the knockdown effect of YAF2 on ET-induced TP53 activation. Finally, impaired apoptosis upon PDCD5 ablation was substantially rescued by restoration of PDCD5WT but not YAF2-interacting defective PDCD5E4D nor TP53-interacting defective PDCD5E16D mutant. Our findings uncovered an apoptotic signaling cascade linking YAF2, PDCD5, and TP53 during genotoxic stress responses.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyo-Kyoung
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Jo
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: JaeSung
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Han
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University College of Human Medicine, MI, USA.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Fertility Center of CHA General Hospital, CHA Research Institute, CHA University, Seoul, Republic of Korea. Electronic address: youngsokchoi@cha.ac.kr.
authors.forename: Youngsok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: yhgeun@yuhs.ac.
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; D007976:Leupeptins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; C117283:PDCD5 protein, human; C486488:Pdcd5 protein, mouse; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C104531:YAF2 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Apoptosis; Genotoxic stress; PDCD5; TP53; YAF2