title: Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2.
abstract: SLBP (stem-loop binding protein) is a highly conserved factor necessary for the processing, translation, and degradation of H2AFX and canonical histone mRNAs. We identified the F-box protein cyclin F, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the G2 ubiquitin ligase for SLBP. SLBP interacts with cyclin F via an atypical CY motif, and mutation of this motif prevents SLBP degradation in G2. Expression of an SLBP stable mutant results in increased loading of H2AFX mRNA onto polyribosomes, resulting in increased expression of H2A.X (encoded by H2AFX). Upon genotoxic stress in G2, high levels of H2A.X lead to persistent γH2A.X signaling, high levels of H2A.X phosphorylated on Tyr142, high levels of p53, and induction of apoptosis. We propose that cyclin F co-evolved with the appearance of stem-loops in vertebrate H2AFX mRNA to mediate SLBP degradation, thereby limiting H2A.X synthesis and cell death upon genotoxic stress.
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: John F
authors: JF
authors: Dankert
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: Gergely
authors: G
authors: Rona
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: Linda
authors: L
authors: Clijsters
authors: Department of Microbiology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: Phillip
authors: P
authors: Geter
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: Jeffrey R
authors: JR
authors: Skaar
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Institute for System Genetics, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: Keria
authors: K
authors: Bermudez-Hernandez
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: Elizabeth
authors: E
authors: Sassani
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Institute for System Genetics, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: David
authors: D
authors: Fenyö
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Proteomics Resource Center, Office of Collaborative Science, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: Beatrix
authors: B
authors: Ueberheide
authors: Department of Microbiology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Department of Radiation Oncology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
authors: Robert
authors: R
authors: Schneider
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Howard Hughes Medical Institute, 522 First Avenue, SRB 1107, New York, NY 10016, USA. Electronic address: michele.pagano@nyumc.org.
authors: Michele
authors: M
authors: Pagano
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014982:Xenopus laevis; D015027:Zebrafish; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C503669:CCNF protein, human; D016213:Cyclins; C468783:H2AX protein, human; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; C092663:SLBP protein, human; D039221:mRNA Cleavage and Polyadenylation Factors
keywords: DNA damage response; H2A.X; SLBP; apoptosis; canonical histone mRNA metabolism; cyclin F; genotoxic stress; proteasome; ubiquitin