Chromosome clustering in mitosis by the nuclear protein Ki-67

Abstract

Ki-67 is highly expressed in proliferating cells, a characteristic that made the protein a very important proliferation marker widely used in the clinic. However, the molecular functions and properties of Ki-67 remained quite obscure for a long time. Only recently important discoveries have shed some light on its 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 function in interphase and mitosis. In this review, we discuss the role of Ki-67 during cell division. Specifically, we focus on the importance of Ki-67 in chromosome individualisation at mitotic entry (prometaphase) and its contribution to chromosome clustering and nuclear remodelling during mitotic exit.

Keywords: Ki-67; chromosomes; mitosis.

Figure 1.. Ki-67 depletion leads to abnormal chromosome clustering in metaphase.

(A) Interphase and mitotic stages of HCT116 cells in the presence (Control) or absence (Ki-67 depletion) of Ki-67. Ki-67 in green, tubulin in red and DNA in blue. The panels from left to right present an interphase nucleus (1, 1′), prometaphase (2, 2′), metaphase (3, 3′), anaphase (4, 4′) and telophase (5, 5′). (B) Metaphase chromosomes of HeLa cells with (top panel — Control) or without (bottom panel — Ki-67 depletion) Ki-67 after paraformaldehyde fixation. (C) Electron microscopy images of metaphase chromosomes from HeLa cells with (top panel — Control) or without (bottom panel — Ki-67 depletion) Ki-67. Images are courtesy of Daniel Booth, Nottingham. (D) Metaphase chromosome spreads of nocodazole arrested HeLa cells with (top panel — Control) or without (bottom panel — Ki-67 depletion) Ki-67.

Figure 2.. A charge-dynamic model for Ki-67 function during mitosis.

(A) Schematic diagram of Ki-67 and its domains. The numbers indicate the amino acids. (B) Lollypop graph representing all the known phosphorylation sites (blue), the tandem repeats (K1: green), the FHA domain (F: light blue) and the PP1 binding site (P: orange) (from https://www.phosphosite.org). (C) Table indicating the net charge of Ki-67 when de-phosphorylated or phosphorylated. (D) Diagram showing the localisation of Ki-67 (green) during mitotic progression. (E) Scheme representing a possible model for a repulsive function of Ki-67(green) in early mitosis and a cohesive function in late mitosis. Phosphorylations are represented by the red circles.