Functional impact of Aurora A-mediated phosphorylation of HP1γ at serine 83 during cell cycle progression

Epigenetics & Chromatin

Gwen Lomberk¹  Raul Urrutia¹  Juan Iovanna⁵  Ezequiel Calvo³  Guillermo Urrutia²  Angela J Mathison²  Seungmae Seo²  Phoebe Leonard⁴  Adrienne Grzenda² 

[1] Translational Epigenomics Program, Center for Individualized Medicine, Rochester, MN 55905, USA;Laboratory of Epigenetics and Chromatin Dynamics, GIH Division, Department of Medicine, Biochemistry and Molecular Biology, Guggenheim 10, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA;Molecular Endocrinology and Oncology Research Center, Centre Hospitalier de l’Universite Laval (CHUL) Research Center, Quebec, QC G1V 4G2, Canada;Department of Obstetrics and Gynecology, Guggenheim 10, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA;Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 624, Stress Cellulaire, 163 Avenue de Luminy, Case 915, Parc Scientifique et Technologique de Luminy, 13288, Marseille Cedex 9, France

关键词: Centrosome;    Spindle pole;    Epigenetics;    Aurora kinase;    Mitosis;    Heterochromatin protein 1 (HP1);   

Others  :  810047
DOI  :  10.1186/1756-8935-6-21

 received in 2013-02-14, accepted in 2013-06-14,  发布年份 2013

【 摘 要 】

Background

Previous elegant studies performed in the fission yeast Schizosaccharomyces pombe have identified a requirement for heterochromatin protein 1 (HP1) for spindle pole formation and appropriate cell division. In mammalian cells, HP1γ has been implicated in both somatic and germ cell proliferation. High levels of HP1γ protein associate with enhanced cell proliferation and oncogenesis, while its genetic inactivation results in meiotic and mitotic failure. However, the regulation of HP1γ by kinases, critical for supporting mitotic progression, remains to be fully characterized.

Results

We report for the first time that during mitotic cell division, HP1γ colocalizes and is phosphorylated at serine 83 (Ser⁸³) in G₂/M phase by Aurora A. Since Aurora A regulates both cell proliferation and mitotic aberrations, we evaluated the role of HP1γ in the regulation of these phenomena using siRNA-mediated knockdown, as well as phosphomimetic and nonphosphorylatable site-directed mutants. We found that genetic downregulation of HP1γ, which decreases the levels of phosphorylation of HP1γ at Ser⁸³ (P-Ser⁸³-HP1γ), results in mitotic aberrations that can be rescued by reintroducing wild type HP1γ, but not the nonphosphorylatable S83A-HP1γ mutant. In addition, proliferation assays showed that the phosphomimetic S83D-HP1γ increases 5-ethynyl-2´-deoxyuridine (EdU) incorporation, whereas the nonphosphorylatable S83A-HP1γ mutant abrogates this effect. Genome-wide expression profiling revealed that the effects of these mutants on mitotic functions are congruently reflected in G₂/M gene expression networks in a manner that mimics the on and off states for P-Ser⁸³-HP1γ.

Conclusions

This is the first description of a mitotic Aurora A-HP1γ pathway, whose integrity is necessary for the execution of proper somatic cell division, providing insight into specific types of posttranslational modifications that associate to distinct functional outcomes of this important chromatin protein.

【 授权许可】

   
2013 Grzenda et al.; licensee BioMed Central Ltd.

【 图 表 】

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