Polar Chromosomes—Challenges of a Risky Path

Abstract

The process of chromosome congression and alignment is at the core of mitotic fidelity. In this review, we discuss distinct spatial routes that the chromosomes take to align during prometaphase, which are characterized by distinct biomolecular requirements. Peripheral polar chromosomes are an intriguing case as their alignment depends on the activity of kinetochore motors, polar ejection forces, and a transition from lateral to end-on attachments to microtubules, all of which can result in the delayed alignment of these chromosomes. Due to their undesirable position close to and often behind the spindle pole, these chromosomes may be particularly prone to the formation of erroneous kinetochore-microtubule interactions, such as merotelic attachments. To prevent such errors, the cell employs intricate mechanisms to preposition the spindle poles with respect to chromosomes, ensure the formation of end-on attachments in restricted spindle regions, repair faulty attachments by error correction mechanisms, and delay segregation by the spindle assembly checkpoint. Despite this protective machinery, there are several ways in which polar chromosomes can fail in alignment, mis-segregate, and lead to aneuploidy. In agreement with this, polar chromosomes are present in certain tumors and may even be involved in the process of tumorigenesis.

Nuclear chromosome locations dictate segregation error frequencies

“…9). We propose that peripheral chromosomes mis-segregate more often than central ones because they need to travel greater distances to reach the metaphase plate, more regularly undergo lateral or merotelic microtubule interactions and/or experience additional delays by being located behind spindle poles [45][46][47][48][49] . It may therefore be a common outcome of processes that cause chromosomal instability, consistent with occurence of biased mi-segregations when we disrupt the SAC, attachment error correction or microtubule dynamics.…”

Chromosome Inequality: Causes and Consequences of Non-Random Segregation Errors in Mitosis and Meiosis

“…These movements are generated by the depolymerization or polymerization of microtubules, but also by microtubule motors such as CENP-E and dynein, which allow for the gliding of chromosomes on microtubules. Chromosomes located in the center of the nucleus almost instantaneously acquire the proper end-on attachments, meaning interactions of kinetochores with the +-ends of microtubules, and therefore achieve correct biorientation without much need for error-correction mechanisms [ 73 ]. However, the more peripheral chromosomes tend to first connect to the lattices of microtubules, and need the help of motor proteins and attachment error-correction mechanisms for conversion to end-on interactions and correct biorientation [ 72 , 74 , 75 , 76 ].…”

“…Because of this, peripheral and thus larger chromosomes often end up behind the poles at the start of mitosis [ 74 , 115 ]. In turn, they need to travel a longer distance to the metaphase plate, are more likely to make non-amphitelic attachments (such as lateral or erroneous ones) [ 73 , 74 , 116 ], or might have difficulties crossing centrosomes. They thus need more time to become bioriented, in contrast to the almost instantaneously bioriented central chromosomes [ 117 ].…”

GPER1 links estrogens to centrosome amplification and chromosomal instability in human colon cells

“…Strikingly, chromosome alignment defects frequently accompanied the formation of chromosome bridges ( Fig S4C , hash and S4F ) and chromosome laggards during anaphase ( Fig S4C , arrows). This prompted us to examine whether transient multipolarity after (xeno)estrogen treatment and chromosome alignment defects drive the formation of lagging chromosomes, as expected ( 3 , 59 ). We therefore synchronized HCT116, HCT-15, and RKO in the anaphase of mitosis using a double thymidine block ( Fig S4G ) and determined the amount of cells with lagging chromosomes.…”

“…). This prompted us to examine whether transient multipolarity after (xeno)estrogen treatment and chromosome alignment defects drive the formation of lagging chromosomes, as expected (3,59). We therefore synchronized HCT116, HCT-15, and RKO in the anaphase of mitosis using a double thymidine block (Fig S4G ) and determined the amount of cells with lagging chromosomes.…”