The multifaceted roles of PLK4

点击翻译按钮获取中文摘要

Years of carefully planned and carried out experiments has determined that the protein called Polo like kinase 4 (PLK4), is a major regulator of centrosome duplication. Centrosomes are small organelles, which are involved in ensuring that the genetic information in cells is passed on equally when a cell divides. PLK4 is a member of a group of proteins known as kinases. These proteins modify the structure and thereby the function or activity of proteins that they interact with. We and others have focused on establishing that alterations of PLK4 levels, either due to an increase or a decrease, have a detrimental effect on cells. PLK4 plays an important role during development, as mouse lacking one allele of plk4 (resulting in lower levels) arrest at day 7.5 of embryonic development. Thus the next question has become what are PLK4 interacting partners and which pathways are affected by changes in PLK4 levels? Data from our NSERC program has characterized interactions between PLK4 and proteins that function in playing a role in how a cell responds to DNA damage. Our recent results in frog embryos indicate a major and conserved role for PLK4 during embryonic development. We also have evidence that PLK4 function is regulated at an epigenetic level and that it may play a role in epigenetic regulation itself. Epigenetics encompasses heritable changes that are not caused by changes in the DNA sequence. Specifically, we were the first to find that PLK4 levels are controlled by promoter methylation, an epigenetic mechanism. We have also found that PLK4 interacts with proteins involved in epigenetic regulation. In the current proposal we will be characterizing PLK4 interactions at the protein level and also addressing the exciting possibility of identifying novel PLK4 interacting partners. Our goal and focus throughout this research program is to delineate the function(s) of PLK4 during embryonic development, epigenetic regulation and the response to DNA damage. Hypothesis: PLK4 plays unique roles in epigenetic regulation, in DNA damage pathways and during development. Short-term objectives: I. Determine whether PLK4 is an essential component of epigenetic regulation and/or the DNA damage response; II. Determine the role of PLK4 during lens placode formation and somitogenesis; III. To further understand the function of PLK4, we will use a novel approach to identify PLK4 interacting partners. Long term objective: To gain a more complete understanding of the roles that PLK4, a Ser/Thr kinase, plays in the cell. Our data has revealed novel areas for PLK4 function. This research program seeks to resolve the molecular complexities and consequences associated with proper PLK4 function; data which is essential for the understanding of regulatory mechanisms in normally functioning cells.