Nuclear envelope assembly defects link mitotic errors to chromothripsis
Posted on: 14 March 2018
Preprint posted on 11 February 2018
Article now published in Nature at http://dx.doi.org/10.1038/s41586-018-0534-z
Never late is better: spindle microtubules force lagging chromosomes to assemble defective micronuclei
Selected by Dey Lab
Categories: biochemistry, cancer biology, cell biology
Context
De-condensing chromosomes recruit membranes and nuclear envelope (NE) proteins upon mitotic exit to reform the intact nuclear boundary that encircles both daughter genomes. Even lagging chromosomes will attempt to do this, but the nuclear envelopes of the ensuing “micronuclei” are prone to a loss of integrity. This exposes chromosomal DNA to the cytoplasm, with deleterious consequences, including a cascade of catastrophic chromosomal rearrangements, known as chromothripsis1. The authors of this preprint investigate NE assembly around lagging chromosomes to understand the molecular basis for micronuclear defects.
Key findings
The authors distinguish between two pools of NE proteins at mitotic exit: proteins like emerin and barrier-to-autointegration factor (BAF) that cluster on chromosomes close to microtubules at this stage2 (referred to as “core” in the preprint), and a second group that includes nuclear pore complex (NPC) components that segregate away from microtubules (“non-core”). Lagging chromosomes that are generated by release from mitotic arrest (or by inhibition of the spindle assembly checkpoint) recruit only core NE. The resulting micronuclei exhibit import defects, which in turn exacerbates the problem by further preventing the accumulation of key nuclear proteins. It has been suggested that segregating chromosomes are continuously monitored by an Aurora B gradient3– however, the authors find that Aurora B inhibition only rescues non-core NE assembly if it takes place before chromosome separation. They go on to show that this effect is likely mediated via a direct coupling between microtubules and NE assembly, rather than spatial signalling from chromosomes. In a final, direct demonstration in support of this hypothesis, artificially forcing chromosomes to the periphery of the spindle largely rescues the defects.
Why I chose it
Recently, Vietri and colleagues4 showed that the ESCRTIII complex interacts with the microtubule-severing protein Spastin to tightly couple spindle disassembly with sealing of the new nuclear membrane. This preprint adds a new dimension to this picture: proper NE composition, including the assembly of functional nuclear pores, also depends on timely spindle disassembly. Taken together, these findings suggest that the critical player that coordinates segregation of the genetic material with its irreversible compartmentalisation is the very structure of the spindle itself- not, in fact, a complex spatial signalling network that monitors chromosome position. This model could drive a paradigm shift in the way we view the common underlying principles of mitotic exit across eukaryotes.
What next?
As the authors also ask in their discussion- is the barrier to nuclear pore assembly on lagging chromosomes a purely physical (steric) consequence of microtubule-chromosome or microtubule-membrane contacts? If the sequential reconstruction of the NE is choreographed by fine spindle structure, could specific perturbations of spindle geometry (physical confinement, induced mono-polar spindles) produce predictable effects on NE composition? Don’t miss the evolving discussion on the consequences of this work in the bioRxiv comments section!
References:
- Zhang, C.-Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015).
- Haraguchi, T. et al. Live cell imaging and electron microscopy reveal dynamic processes of BAF-directed nuclear envelope assembly. J. Cell Sci. 121, 2540–54 (2008).
- Afonso, O. et al. Feedback control of chromosome separation by a midzone Aurora B gradient. Science (80-. ). 345, 332–336 (2014).
- Vietri, M. et al. Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing. Nature 522, 231–235 (2015).
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