WAPL-mediated removal of cohesin protects against segregation errors and aneuploidy.
The classical X shape of mitotic human chromosomes is the consequence of two distinct waves of cohesin removal. First, during prophase and prometaphase, the bulk of cohesin is driven from chromosome arms by the cohesin antagonist WAPL. This arm-specific cohesin removal is referred to as the prophase pathway [1-4]. The subsequent cleavage of the remaining centromeric cohesin by Separase is known to be the trigger for anaphase onset [5-7]. Remarkably the biological purpose of the prophase pathway is unknown. We find that this pathway is essential for two key mitotic processes. First, it is important to focus Aurora B at centromeres to allow efficient correction of erroneous microtubule-kinetochore attachments. In addition, it is required to facilitate the timely decatenation of sister chromatids. As a consequence, WAPL-depleted cells undergo anaphase with segregation errors, including both lagging chromosomes and catenanes, resulting in micronuclei and DNA damage. Stable WAPL depletion arrests cells in a p53-dependent manner but causes p53-deficient cells to become highly aneuploid. Our data show that the WAPL-dependent prophase pathway is essential for proper chromosome segregation and is crucial to maintain genomic integrity.
Department of Cell Biology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Judith H I
JH
Haarhuis
Ahmed M O
AM
Elbatsh
Bram
B
van den Broek
Daniel
D
Camps
Hasan
H
Erkan
Kees
K
Jalink
René H
RH
Medema
Benjamin D
BD
Rowland
D000782:Aneuploidy; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002503:Centromere / Q000378:metabolism; D002842:Chromatids / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D020090:Chromosome Segregation; D002877:Chromosomes, Human / Q000378:metabolism; D006801:Humans; D008858:Microscopy, Phase-Contrast; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011418:Prophase; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D055213:Retinal Pigment Epithelium; D000097722:Cohesins
D064107:Aurora Kinase B; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000097722:Cohesins; C488092:WAPL protein, human; C576921:AURKB protein, human