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Mol Cell. 2016 Nov 3;64(3):507-519. doi: 10.1016/j.molcel.2016.09.010. Epub 2016 Oct 20.

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2.

Author information

1
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.
2
Department of Microbiology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
3
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.
4
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.
5
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.
6
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.

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.

KEYWORDS:

DNA damage response; H2A.X; SLBP; apoptosis; canonical histone mRNA metabolism; cyclin F; genotoxic stress; proteasome; ubiquitin

PMID:
27773672
PMCID:
PMC5097008
DOI:
10.1016/j.molcel.2016.09.010
[Indexed for MEDLINE]
Free PMC Article

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