Work

hSpindly dynamics modulate spindle assembly checkpoint signaling, promoting resistance to mitotic inhibitors

Year: 2026

Type: article

Abstract: The spindle assembly checkpoint (SAC) prevents sister chromatids separation until all chromosomes are properly attached to spindle microtubules and bi-oriented. SAC controls the metaphase-to-anaphase transition by inhibiting the anaphase promoting complex/cyclosome (APC/C). A critical step in this process is the recruitment of the Mad1-Mad2 complex to unattached kinetochores mediated by the KBB pathway (KNL1-Bub3-Bub1) and the RZZ pathway (Rod-Zw10-Zwilch). Here, we show that hSpindly contributes to the regulation of Mad1-Mad2 recruitment through the RZZ pathway. We demonstrate that hSpindly is a dynamic protein that oligomerizes at unattached kinetochores, and we identify threonine 552 as a key residue controlling its mobility and function. A non-phosphorylatable mutant (T552A) displays reduced dynamics at kinetochores, impairs SAC signaling, and increases cellular resistance to antimitotic drugs. Altogether, our findings identify hSpindly as a dynamic regulator of SAC signaling and potential therapeutic target for overcoming resistance to mitotic inhibitors.

Source: iScience

DOI: 10.1016/j.isci.2026.116312

Authors: Mar Mora-Santos, Joaquín Herrero-Ruiz, Dirk Fennema-Galparsoro, Alejandro Belmonte-Fernández, Nuria Ferrandiz, Francisco Romero

Institutions: Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Centro de Investigación del Cáncer

Language: English

Topic: Microtubule and mitosis dynamics

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,240