Functional impact of Aurora A-mediated phosphorylation of HP1? at serine 83 during cell cycle progression.

ABSTRACT:

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, HP1? has been implicated in both somatic and germ cell proliferation. High levels of HP1? protein associate with enhanced cell proliferation and oncogenesis, while its genetic inactivation results in meiotic and mitotic failure. However, the regulation of HP1? by kinases, critical for supporting mitotic progression, remains to be fully characterized.

Results

We report for the first time that during mitotic cell division, HP1? 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 HP1? 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 HP1?, which decreases the levels of phosphorylation of HP1? at Ser83 (P-Ser83-HP1?), results in mitotic aberrations that can be rescued by reintroducing wild type HP1?, but not the nonphosphorylatable S83A-HP1? mutant. In addition, proliferation assays showed that the phosphomimetic S83D-HP1? increases 5-ethynyl-2´-deoxyuridine (EdU) incorporation, whereas the nonphosphorylatable S83A-HP1? 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-HP1?.

Conclusions

This is the first description of a mitotic Aurora A-HP1? 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.

SUBMITTER: Grzenda A 

PROVIDER: S-EPMC3707784 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature