Mitotic catenation is monitored and resolved by a PKCε-regulated pathway

TY - JOUR

T1 - Mitotic catenation is monitored and resolved by a PKCε-regulated pathway

AU - Brownlow, Nicola

AU - Pike, Tanya

AU - Zicha, Daniel

AU - Collinson, Lucy

AU - Parker, Peter J

PY - 2014/12/8

Y1 - 2014/12/8

N2 - Exit from mitosis is controlled by silencing of the spindle assembly checkpoint (SAC). It is important that preceding exit, all sister chromatid pairs are correctly bioriented, and that residual catenation is resolved, permitting complete sister chromatid separation in the ensuing anaphase. Here we determine that the metaphase response to catenation in mammalian cells operates through PKCε. The PKCε-controlled pathway regulates exit from the SAC only when mitotic cells are challenged by retained catenation and this delayed exit is characterized by BubR1-high and Mad2-low kinetochores. In addition, we show that this pathway is necessary to facilitate resolution of retained catenanes in mitosis. When delayed by catenation in mitosis, inhibition of PKCε results in premature entry into anaphase with PICH-positive strands and chromosome bridging. These findings demonstrate the importance of PKCε-mediated regulation in protection from loss of chromosome integrity in cells failing to resolve catenation in G2.

AB - Exit from mitosis is controlled by silencing of the spindle assembly checkpoint (SAC). It is important that preceding exit, all sister chromatid pairs are correctly bioriented, and that residual catenation is resolved, permitting complete sister chromatid separation in the ensuing anaphase. Here we determine that the metaphase response to catenation in mammalian cells operates through PKCε. The PKCε-controlled pathway regulates exit from the SAC only when mitotic cells are challenged by retained catenation and this delayed exit is characterized by BubR1-high and Mad2-low kinetochores. In addition, we show that this pathway is necessary to facilitate resolution of retained catenanes in mitosis. When delayed by catenation in mitosis, inhibition of PKCε results in premature entry into anaphase with PICH-positive strands and chromosome bridging. These findings demonstrate the importance of PKCε-mediated regulation in protection from loss of chromosome integrity in cells failing to resolve catenation in G2.

KW - Cell Cycle Proteins/metabolism

KW - Cell Separation

KW - Chromosome Segregation

KW - Chromosomes/ultrastructure

KW - Dyneins/metabolism

KW - Flow Cytometry

KW - G2 Phase

KW - Gene Silencing

KW - Green Fluorescent Proteins/metabolism

KW - HEK293 Cells

KW - HeLa Cells

KW - Humans

KW - Kinetochores/metabolism

KW - Metaphase

KW - Microscopy, Fluorescence

KW - Mitosis

KW - Neoplasms/metabolism

KW - Protein Kinase C-epsilon/metabolism

KW - RNA, Small Interfering/metabolism

KW - Sister Chromatid Exchange

KW - Spindle Apparatus

U2 - 10.1038/ncomms6685

DO - 10.1038/ncomms6685

M3 - Article

C2 - 25483024

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5685

ER -