Biology subjects

Compton, D.

Publications and source records attributed to Compton, D..

3 recordsLinked to original sources

bioRxiv2026

Countervailing effects of cyclin isoforms A and B during mitosis

Faithful chromosome segregation requires the spatial and temporal remodeling of cell structures driven largely by cyclin-dependent kinase (Cdk) activity. In some experimental systems the timely elevation of one cyclin isoform is sufficient to support mitotic entry and progression. In human somatic cells, however, three cyclins - Cyclin A2, Cyclin B1, and Cyclin B2 - are present at mitotic entry, and their distinct contributions during mitosis remain largely unclear. We demonstrate that Cyclin A2 promotes the kinetochore localization of Cyclin B1, Cyclin B2 and the fibrous corona component CENPF, while suppressing recruitment of the kinetochore-microtubule (k-MT) stabilizer Astrin. Extending Cyclin A2 into metaphase by expressing a non-degradable mutant causes persistent kinetochore localization of Cyclin B1, Cyclin B2, and CENPF. Conversely, Cyclin B1 limits kinetochore localization of Cyclin B2 and CENPF, promotes Astrin recruitment, and stabilizes k-MT attachments and Cyclin B1 overexpression further reduces kinetochore localization of CENPF during prometaphase. These findings reveal an interdependence among mitotic cyclins in early mitosis and the countervailing activities of Cyclin A2 versus Cyclin B1/B2 in regulating key mitotic events. We propose that this circuitry enforces a switch-like transition from prometaphase - marked by corona assembly and high k-MT turnover - to metaphase - marked by corona disassembly, stabilization of end-on k-MT attachments, and eventual spindle assembly checkpoint satisfaction - to choreograph the structural changes required to ensure faithful chromosome segregation.

cell biology↗

bioRxiv2023

Cyclin A/Cdk1 promotes chromosome alignment and timely mitotic progression

To ensure genomic fidelity a series of spatially and temporally coordinated events are executed during prometaphase of mitosis, including bipolar spindle formation, chromosome attachment to spindle microtubules at kinetochores, the correction of erroneous kinetochore-microtubule (k-MT) attachments, and chromosome congression to the spindle equator. Cyclin A/Cdk1 kinase plays a key role in destabilizing k-MT attachments during prometaphase to promote correction of erroneous k-MT attachments. However, it is unknown if Cyclin A/Cdk1 kinase regulates other events during prometaphase. Here, we investigate additional roles of Cyclin A/Cdk1 in prometaphase by using an siRNA knockdown strategy to deplete endogenous Cyclin A from human cells. We find that depleting Cyclin A significantly extends mitotic duration, specifically prometaphase, because chromosome alignment is delayed. Unaligned chromosomes display erroneous monotelic, syntelic, or lateral k-MT attachments suggesting that bioriented k-MT attachment formation is delayed in the absence of Cyclin A. Mechanistically, chromosome alignment is likely impaired because the localization of the kinetochore proteins BUB1 kinase, KNL1, and MPS1 kinase are reduced in Cyclin A-depleted cells. Moreover, we find that Cyclin A promotes BUB1 kinetochore localization independently of its role in destabilizing k-MT attachments. Thus, Cyclin A/Cdk1 facilitates chromosome alignment during prometaphase to support timely mitotic progression.

cell biology↗

bioRxiv2022

A Pluripotent Developmental State Confers a Low Fidelity of Chromosome Segregation

Human pluripotent stem cells (hPSCs) frequently become aneuploid with abnormal chromosome numbers due to mitotic chromosome segregation errors during propagation in culture. Yet, we do not understand why hPSCs exhibit a low mitotic fidelity. Here we investigate the mechanisms responsible for mitotic errors in hPSCs and show that the primary cause is lagging chromosomes with improper merotelic chromosome microtubule attachments in anaphase. Accordingly, we can improve merotelic error correction and reduce lagging chromosome rates in hPSCs using small molecules that prolong mitotic duration or destabilize chromosome microtubule attachments providing chemical strategies to preserve genome stability. Strikingly, we also demonstrate that mitotic error rates correlate with developmental potential decreasing upon differentiation and loss of pluripotency and conversely increasing after reprogramming to a pluripotent state. Thus, chromosome segregation fidelity is inherently low in hPSCs and depends on developmental state in normal human cells.

cell biology↗