Micronuclei from misaligned chromosomes that satisfy the spindle assembly checkpoint in cancer cells

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Gomes, AM (Author) Other; Orr, B (Author) Other; Novais Cruz, M (Author) Other; De Sousa, F (Author) Other; Macario Monteiro, J (Author) Other; Carolina Lemos (Author) ICBAS; Ferras, C (Author) Other; Helder Maiato (Author) FMUP

Journal

Title: Current Biology

Vol. 32

Pages: 4240-+

ISSN: 0960-9822

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 7 Citations

Scopus - 6 Citations

Other information

Authenticus ID: P-00X-B00

DOI: 10.1016/j.cub.2022.08.026

Abstract (EN): Chromosome alignment to the spindle equator is a hallmark of mitosis thought to promote chromosome segregation fidelity in metazoans. Yet chromosome alignment is only indirectly supervised by the spindle assembly checkpoint (SAC) as a byproduct of chromosome bi-orientation, and the consequences of defective chromosome alignment remain unclear. Here, we investigated how human cells respond to chromosome alignment defects of distinct molecular nature by following the fate of live HeLa cells after RNAi-mediated depletion of 125 proteins previously implicated in chromosome alignment. We confirmed chromosome alignment defects upon depletion of 108/125 proteins. Surprisingly, in all confirmed cases, depleted cells frequently entered anaphase after a delay with misaligned chromosomes. Using depletion of prototype proteins resulting in defective chromosome alignment, we show that misaligned chromosomes often satisfy the SAC and directly missegregate without lagging behind in anaphase. In-depth analysis of specific molecular perturbations that prevent proper kinetochore-microtubule attachments revealed that misaligned chromosomes that missegregate frequently result in micronuclei. Higher-resolution live-cell imaging indicated that, contrary to most anaphase lagging chromosomes that correct and reintegrate the main nuclei, misaligned chromosomes are a strong predictor of micronuclei formation in a cancer cell model of chromosomal instability, but not in non-transformed near-diploid cells. We provide evidence supporting that intrinsic differences in kinetochore-microtubule attachment stability on misaligned chromosomes account for this distinct outcome. Thus, misaligned chromosomes that satisfy the SAC may represent a previously over-looked mechanism driving chromosomal/genomic instability during cancer cell division, and we unveil genetic conditions predisposing for these events.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 21