A new pathway regulating mitosis
Addition of an ubiquitin group on PLK1 kinase triggers its removal from the kinetochore and therefore allows stabilization of the kinetochore-microtubules attachments. © Nat. Cell Biol.
Nat Cell Biol Apr 2013
March 3, 2013
Izabela Sumara’s team at the IGBMC identified a new pathway regulating spatiotemporal distribution of PLK1 kinase, which is essential for mitotic progression. A study published on March 3rd, 2013 in Nat. Cell Biol.
Every day, about a billion out of 10,000 billion of cells composing human body have to be renewed. Several steps govern the transition from one into two identical cells. First, the DNA is duplicated during S-phase and then the two identical copies of DNA form chromosomes that are separated during mitosis. A crucial step in mitosis is the alignment of chromosomes at the center of the cell. At that point, a cable network, composed of microtubules, so called mitotic spindle is formed. The mitotic spindle makes contacts to kinetochores, the structures present on all chromosomes, thereby allowing their segregation to two daugther cells. This particular step is subjected to a precise regulation, as an error in the distribution of the genetic material could lead to genomic instability and as a consequence, tumorigenesis.
PLK1 is a protein kinase known to play a key role in the process of chromosome alignment during mitosis. In its absence, the cell division cannot continue, leading to cell death. At first, PLK1 accumulates at kinetochores, but in order to pursue the course of mitosis, the kinase has to be removed from kinetochores at the later stages. Although the spatiotemporal distribution of PLK1 is known, the underlying molecular mechanisms remained unclear until now. Izabela Sumara’s team at the IGBMC identified a novel mitotic pathway, based on CUL3 ubiquitin E3 ligase, regulating PLK1 in time and space.
The scientists showed that CUL3 interacts with PLK1 via an adaptor protein, KLHL22. When CUL3-complex binds to PLK1, it catalyzes addition of one ubiquitin molecule, which triggers PLK1 removal from kinetochores allowing for stabilization of the kinetochore-microtubules attachments. This novel pathway is important for mitotic progression as inactivation of CUL3-complex leads to severe defects in chromosome segregation and cellular death. These results also show that not only correct localization of the mitotic kinase but also its timely removal from the kinetochores is crucial for mitotic progression.
Thus, these studies establish a critical role of the non-proteolytic ubiquitin signaling in a spatio-temporal regulation of mitosis and pave the way for future studies towards a better understanding of ubiquitin post-translation modifications. CUL3-KLHL22 E3-ligase complex appears to have specific affinities to other kinases, suggesting that the discovered mechanism could be more general. Since many mitotic kinases, including PLK1, are deregulated in cancer, a better knowledge of CUL3 pathways may therefore help to develop future anti-cancer therapeutic strategies.