GTSE1 tunes microtubule stability for chromosome alignment and segregation by inhibiting the microtubule depolymerase
Shweta Bendre1, Arnaud Rondelet1, Conrad Hall2
1Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
Abstract:
The dynamic regulation of microtubules (MTs) during mitosis is critical for accurate chromosome segregation and genome stability. Cancer cell lines with hyperstabilized kinetochore MTs have increased segregation errors and elevated chromosomal instability (CIN), but the genetic defects responsible remain largely unknown. The MT depolymerase MCAK (mitotic centromere-associated kinesin) can influence CIN through its impact on MT stability, but how its potent activity is controlled in cells remains unclear. In this study, we show that GTSE1, a protein found overexpressed in aneuploid cancer cell lines and tumors, regulates MT stability during mitosis by inhibiting MCAK MT depolymerase activity. Cells lacking GTSE1 have defects in chromosome alignment and spindle positioning as a result of MT instability caused by excess MCAK activity. Reducing GTSE1 levels in CIN cancer cell lines reduces chromosome missegregation defects, whereas artificially inducing GTSE1 levels in chromosomally stable cells elevates chromosome missegregation and CIN. Thus, GTSE1 inhibition of MCAK activity regulates the balance of MT stability that determines the fidelity of chromosome alignment, segregation, and chromosomal stability.
Insights
GTSE1 protein regulates microtubule (MT) stability by inhibiting MCAK activity during mitosis. This control is crucial for accurate chromosome segregation and preventing chromosomal instability (CIN) in cancer cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Dynamic regulation of microtubules (MTs) is essential for mitosis and genome stability.
- Hyperstabilized MTs in cancer cells correlate with increased chromosome segregation errors and chromosomal instability (CIN).
- The MT depolymerase MCAK influences CIN, but its precise regulation remains unclear.
Purpose of the Study:
- To investigate the role of GTSE1 in regulating MT stability during mitosis.
- To determine how GTSE1 affects MCAK activity and its impact on chromosome segregation.
- To explore GTSE1's potential as a therapeutic target in cancer.
Main Methods:
- Investigated GTSE1 function in cancer cell lines and tumors.
- Assessed the impact of GTSE1 on MT stability and MCAK activity.
- Analyzed chromosome alignment, spindle positioning, and CIN in cells with altered GTSE1 levels.
Main Results:
- GTSE1 is overexpressed in aneuploid cancer cells and inhibits MCAK MT depolymerase activity.
- Loss of GTSE1 leads to MT instability, causing chromosome alignment and spindle positioning defects.
- Reducing GTSE1 in CIN cancer cells decreased missegregation; increasing GTSE1 in stable cells elevated missegregation and CIN.
Conclusions:
- GTSE1 acts as a crucial regulator of MT stability by inhibiting MCAK.
- GTSE1's regulation of MT dynamics is vital for accurate chromosome segregation and maintaining genome stability.
- GTSE1 modulation impacts CIN, suggesting its potential role in cancer progression and therapeutic strategies.
Related Concept Videos
02:17Microtubule Instability
02:17Microtubule Instability
02:19The Spindle Assembly Checkpoint
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
02:19The Spindle Assembly Checkpoint
01:45Destabilization of Microtubules
01:15Drugs that Stabilize Microtubules