The role of Ki-67 in cell cycle progression

Abstract

Ki-67 is highly expressed in proliferating cells, a characteristic that made the protein a very important marker widely used in the clinic. However, its molecular functions and properties have remained quite obscure for a long time. Only recently important discoveries have shed some light on Ki-67 function and shown that Ki-67 has a major role in the formation of mitotic chromosome periphery compartment, it is associated with protein phosphatase one (PP1) and regulates chromatin structure in both interphase and mitosis. However, it is still difficult to understand the specific molecular function of this protein since the different phenotypes could be the outcome of secondary effects. In fact, the studies so far conducted have used either RNAi or knock-out cells: the former could lead to phenotypes which are the sum of a cascade of complex events while the latter could be the outcome of compensatory mechanisms taking place. Here, by using Auxin-inducible-degron (AID) system, we have unveiled a new function of Ki-67 at G1/S transition and DNA replication. Loss of the protein leads to DNA damage, and activation of the interferon α/β pathway, resulting in severe replication delay. Despite that, the cells are completing DNA replication but with cohesion defects and under-replicated DNA. Ki-67 degradation during mitosis leads to G1 arrest through the activation of the G1 checkpoint and the downregulation of essential genes necessary for cell cycle progression. Ki-67 is removed for a prolonged time, cells block in G1 as a response to Ki-67 loss, but then adapt to this loss and re-enter the cell cycle. These cells display many defects including increase in aneuploidy, elevated ER stress and reduced ability to metastasise.