Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes

Abstract

Errors in mitosis that cause chromosome missegregation lead to aneuploidy and micronucleus formation, which are associated with cancer. Accurate segregation requires the alignment of all chromosomes by the mitotic spindle at the metaphase plate, and any misalignment must be corrected before anaphase is triggered. The spindle is situated in a membrane-free “exclusion zone”; beyond this zone, endomembranes (mainly endoplasmic reticulum) are densely packed. We investigated what happens to misaligned chromosomes localized beyond the exclusion zone. Here we show that such chromosomes become ensheathed in multiple layers of endomembranes. Chromosome ensheathing delays mitosis and increases the frequency of chromosome missegregation and micronucleus formation. We use an induced organelle relocalization strategy in live cells to show that clearance of endomembranes allows for the rescue of chromosomes that were destined for missegregation. Our findings indicate that endomembranes promote the missegregation of misaligned chromosomes that are outside the exclusion zone and therefore constitute a risk factor for aneuploidy.

Polar Chromosomes—Challenges of a Risky Path

“…These findings imply that only a low number of unattached polar chromosomes could induce moderate mitotic delays, which would lead to mis-segregation of unaligned chromosomes. Accordingly, studies that used CENP-E perturbations reported mis-segregation of one or a few unaligned polar chromosomes after moderate mitotic delays in HeLa [103], RPE1 [188,189], and mouse embryonic cells [190]. A similar phenomenon was observed after treatment of cells with nanomolar doses of nocodazole [186].…”

“…Interestingly, the SAC response was robust since Mad1 was recruited on unaligned kinetochores in such cells, and mitotic delays were at the level of a few hours. Moreover, anaphase onset was not the result of 'cohesion fatigue' or 'mitotic slippage' [191,192] since it was preceded by the loss of Mad proteins from unaligned kinetochores, implying that both sister kinetochores acquired endon connections that were able to satisfy the SAC [103,186,188,189]. However, it is unclear what types of attachment could satisfy the SAC at the pole since syntelic, monotelic, and lateral attachments induce a large SAC response [134], although it is possible that the SAC signal wears faster over time if stable end-on attachments are present at one of the sister kinetochores [125,193].…”

“…However, it is unclear what types of attachment could satisfy the SAC at the pole since syntelic, monotelic, and lateral attachments induce a large SAC response [134], although it is possible that the SAC signal wears faster over time if stable end-on attachments are present at one of the sister kinetochores [125,193]. A recent study presented an intriguing model in which difficulties associated with the inability of unaligned chromosomes to congress are not necessarily caused by defects related to MTs, SAC, or motors but rather due to the presence of a complex system of organelle remnants behind the spindle poles, termed endomembranes, which could ensheat polar chromosomes and prevent their efficient capture by MTs, resulting in aneuploidy [189]. However, for definitive conclusions about the mechanisms underlying unaligned chromosome mis-segregation in unperturbed cells, one would need to track the origin and fate of mis-segregations through whole mitosis, similar to what was done recently from metaphase to telophase in human cells [194].…”

Endoplasmic reticulum membranes are continuously required to maintain mitotic spindle size and forces

“…When ER membrane biogenesis is increased by enhanced fatty acid synthesis, this leads to higher viscosity of the cytoplasm and ultimately to chromosome mis-segregation ( Merta et al, 2021 ). Moreover, chromosomes that become unsheathed by the ER are more prone to segregation errors ( Ferrandiz et al, 2022 ). Hence, ER reorganization may be a passive event, required for faithful mitosis and even distribution of this organelle to daughter cells ( Smyth et al, 2015 ).…”

Too close for comfort? Endomembranes promote missegregation by enclosing lost chromosomes

“…To study this, Ferrandiz et al ( 5 ) artificially induced chromosome misalignment through inhibiting centromere-associated protein E (CENP-E), a kinesin-like motor protein that is essential for correct chromosome alignment ( 6 ). In addition, they used a system in which the Y chromosome can be forced to detach from the spindle, resulting in misalignment.…”