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Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2.
- Source :
-
Molecular cell [Mol Cell] 2016 Nov 03; Vol. 64 (3), pp. 507-519. Date of Electronic Publication: 2016 Oct 20. - Publication Year :
- 2016
-
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.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Motifs
Animals
Apoptosis
Binding Sites
Cell Line, Tumor
Cyclins metabolism
Gene Expression Regulation
HEK293 Cells
HeLa Cells
Histones metabolism
Humans
Mice
Nuclear Proteins metabolism
Phosphorylation
Polyribosomes genetics
Polyribosomes metabolism
Protein Binding
Proteolysis
RNA, Messenger metabolism
Rats
Signal Transduction
Xenopus laevis
Zebrafish
mRNA Cleavage and Polyadenylation Factors metabolism
Cyclins genetics
DNA Damage
G2 Phase Cell Cycle Checkpoints genetics
Histones genetics
Nuclear Proteins genetics
RNA, Messenger genetics
mRNA Cleavage and Polyadenylation Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 64
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 27773672
- Full Text :
- https://doi.org/10.1016/j.molcel.2016.09.010