GMCL1 Controls 53BP1 Stability and Modulates Paclitaxel Sensitivity in Cancer DOI Open Access
Yuki Kito, Tania J González-Robles, Sharon Kaisari

et al.

Published: May 23, 2025

Abstract The Mitotic Surveillance Pathway (MSP) monitors the duration of M-phase. Prolonged mitosis, caused by spindle attachment defects or microtubule-targeting drugs such as taxane paclitaxel, induces formation ternary “mitotic stopwatch” complex consisting 53BP1, USP28, and p53. This event protects p53 from degradation, resulting in cell cycle arrest apoptosis daughter cells. In paclitaxel-resistant cancers, cells bypass MSP, enabling unchecked proliferation survival, although underlying mechanisms remain unknown. Here, we demonstrate that 53BP1 physically interacts with GMCL1 but not its paralog, GMCL2, mapped interaction regions on both proteins. CRL3GMCL1 functions a ubiquitin ligase targets for degradation during M phase, impacting levels High expression significantly correlates resistance to paclitaxel cancer lines wild-type p53, including endometrial, breast, upper aerodigestive tract Loss restores sensitivity expressing deficient We propose cancers high levels, CRL3GMCL1-mediated prevents mitotic stopwatch complex, leading sustained proliferation. Finally, our results indicate inhibition represents novel strategy restore resistant cancers.

Language: Английский

GMCL1 Controls 53BP1 Stability and Modulates Paclitaxel Sensitivity in Cancer DOI Open Access
Yuki Kito, Tania J González-Robles, Sharon Kaisari

et al.

Published: May 23, 2025

Abstract The Mitotic Surveillance Pathway (MSP) monitors the duration of M-phase. Prolonged mitosis, caused by spindle attachment defects or microtubule-targeting drugs such as taxane paclitaxel, induces formation ternary “mitotic stopwatch” complex consisting 53BP1, USP28, and p53. This event protects p53 from degradation, resulting in cell cycle arrest apoptosis daughter cells. In paclitaxel-resistant cancers, cells bypass MSP, enabling unchecked proliferation survival, although underlying mechanisms remain unknown. Here, we demonstrate that 53BP1 physically interacts with GMCL1 but not its paralog, GMCL2, mapped interaction regions on both proteins. CRL3GMCL1 functions a ubiquitin ligase targets for degradation during M phase, impacting levels High expression significantly correlates resistance to paclitaxel cancer lines wild-type p53, including endometrial, breast, upper aerodigestive tract Loss restores sensitivity expressing deficient We propose cancers high levels, CRL3GMCL1-mediated prevents mitotic stopwatch complex, leading sustained proliferation. Finally, our results indicate inhibition represents novel strategy restore resistant cancers.

Language: Английский

Citations

0
GMCL1 Controls 53BP1 Stability and Modulates Paclitaxel Sensitivity in Cancer DOI Open Access
Yuki Kito, Tania J González-Robles, Sharon Kaisari

et al.

Published: May 23, 2025

Abstract The Mitotic Surveillance Pathway (MSP) monitors the duration of M-phase. Prolonged mitosis, caused by spindle attachment defects or microtubule-targeting drugs such as taxane paclitaxel, induces formation ternary “mitotic stopwatch” complex consisting 53BP1, USP28, and p53. This event protects p53 from degradation, resulting in cell cycle arrest apoptosis daughter cells. In paclitaxel-resistant cancers, cells bypass MSP, enabling unchecked proliferation survival, although underlying mechanisms remain unknown. Here, we demonstrate that 53BP1 physically interacts with GMCL1 but not its paralog, GMCL2, mapped interaction regions on both proteins. CRL3GMCL1 functions a ubiquitin ligase targets for degradation during M phase, impacting levels High expression significantly correlates resistance to paclitaxel cancer lines wild-type p53, including endometrial, breast, upper aerodigestive tract Loss restores sensitivity expressing deficient We propose cancers high levels, CRL3GMCL1-mediated prevents mitotic stopwatch complex, leading sustained proliferation. Finally, our results indicate inhibition represents novel strategy restore resistant cancers.

Language: Английский

Citations

0