PRBB-CRG Sessions
by Helder Maiato, University of Porto. PT
Abstract
The spindle asembly checkpoint (SAC) is assumed as the sole surveillance mechanisme operating during mitosis to promote chromosome segregation fidelity. However, some mitotic errors stemming from incorrect kinetochore-microtubule attachments satisfy the SAC, thus representing major threats to genomics stability due to the possible gain or loss of specific chromosomes (i.e. aneuploidy) and the formation of micronuclei. Micronuclei have long been used as ganotoxicity biomarkers and were recently implicated in tumor evolution as key intermediates of chromosome shattering events associated with chromothripsis. Surprisingly, we discovered that SAC-invisible errors are more frequent than previously anticipated, even in non-transformed human cells. However, SAC-invisible errors that give rise to lagging chromosomes in anaphase rarely lead to micronuclei formation due to an active surveillance mechanism based on a midzone Aurora B phosphorylation gradient that stabilizes kinetochore-microtubule attachments ans assists spindle forces required for anaphase error connection, while delaying nucelar envelope reassembly on lagging chromosomes independently of microtubule disassembly. On the other hand, we found that contrary to most anaphase lagging chromosomes that correct and reintegrate the main nuclei, chronically misaligned chromosomes often satisfy the SAC and missegregate, representing the most faithful predictor of micronuclei formation in chromosomally unstable cancer cells, but not in non-transformed human cells. Thus, chronically misaligned chromosomes may represent a previosly overlooked mechanism driving chromosomal/genomic instability during cancer cell division, and we unveil genetic conditions predisposing for these events.
