Acetylation of PLK4: a regulator of genome stability
The acetylation of the kinase domain PLK4 regulates the proper formation of two centrioles (green). When this acetylation does not occur, supernumerary centrioles are formed and the cell becomes abnormal.
Oct. 31, 2016
Laszlo Tora's team, in partnership with the Ecole Polytechnique Fédérale de Lausanne (EPFL, Switzerland) have established a link between post-translational modifications of certain proteins and cell division. Published on October 31st, in the journal Nature Communications, their results show that acetylation of the protein kinase PLK4, influences its activity on centrosomes, organelles that are essential to the success of mitosis.
Post-translational modifications in question
Once synthesized, proteins may undergo slight chemical changes called post-translational modifications. These modifications, which can include phosphorylation, methylation, glycosylation, ubiquitination and many others, generally result in modulation of protein function. Among them, acetylation (i.e. addition of an acetyl group) is well known for its role on the histone proteins (DNA compaction proteins) and its involvement in gene regulation, cell cycle control, and DNA replication and repair. This modification, however, also affects many thousands of other proteins for which its role is less clear. The team of Laszlo Tora has focused on the protein targets of two homolog acetyltransferases (proteins responsible for depositing the acetyl modification onto proteins): KAT2A (GCN5) and KAT2B (PCAF). They found nearly 400 proteins that are acetylated by these enzymes, including the protein kinase PLK4, which is already known for its important role in the formation of centrosomes.
The centrosome, seat of cell division
When they are not dividing, animal cells generally have one centrosome, itself composed of two centrioles. The main role of these organelles is to form the mitotic spindle that will guide the distribution of chromosomes during cell division. The precise mechanisms regulating formation and activity of centrosomes are important and potentially offer new therapeutic targets, because abnormal multiplication of centrosomes is often observed in cancer cells.
In partnership with the teams of Peter Gönczy (EPFL) and Annick Dejaegere (IGBMC), the team of Laszlo Tora found at the molecular level that the acetylation of PLK4 by KAT2A/2B had an inhibitory effect on the kinase domain of PLK4, which affected the formation of centrosomes. This mechanism was corroborated by showing that the reduction of KAT2A/2B acetyltransferase activity, lead to the production of supernumerary centrosomes. In conclusion, acetylation of PLK4 by KAT2A or KAT2B negatively regulates the kinase activity of PLK4, and this modification is essential for the formation of centrioles. If PLK4 is not acetylated by KAT2A/2B, then excess centrioles are formed. If deregulated, this mechanism may be involved in tumor progression and thus be targeted for therapeutic developments.