Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death in replication stressed cells results in distinct cellular outcomes depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and cancer genome evolution.
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http://dx.doi.org/10.1038/s41467-019-12255-w | DOI Listing |
Biomed Pharmacother
December 2024
Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea. Electronic address:
Colorectal malignancies associated with KRAS and TP53 mutations led us to investigate the effects of combination therapy targeting KRAS, MEK1, or PLK1 in colorectal cancer. MEK1 is downstream of RAS in the MAPK pathway, whereas PLK1 is a mitotic kinase of the cell cycle activated by MAPK and regulated by p53. Bioinformatics analysis revealed that patients with colorectal cancer had a high expression of MAP2K1 and PLK1.
View Article and Find Full Text PDFCurr Opin Cell Biol
December 2024
Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan. Electronic address:
During mitosis, chromosomes condense, align to form a metaphase plate and segregate to the two daughter cells. Mitosis is one of the most complex recurring transformations in the life of a cell and requires a high degree of reliability to ensure the error-free transmission of genetic information to the next cell generation. An abnormally prolonged mitosis indicates potential defects that compromise genomic integrity.
View Article and Find Full Text PDFNeural Regen Res
November 2025
Department of Neuroscience, Ohio State University, Columbus, OH, USA.
In recent years, the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine. Considering the non-regenerative nature of the mature central nervous system, the concept that "blank" cells could be reprogrammed and functionally integrated into host neural networks remained intriguing. Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells, such as neurons.
View Article and Find Full Text PDFBiomol Ther (Seoul)
January 2025
Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangneung 25457, Republic of Korea.
In cancer cells, survival genes contribute to uncontrolled growth and the survival of malignant cells, leading to tumor progression. Neurons are post-mitotic cells, fully differentiated and non-dividing after neurogenesis and survival genes are essential for cellular longevity and proper functioning of the nervous system. This review explores recent research findings regarding the role of survival genes, particularly DX2, in degenerative neuronal tissue cells and cancer cells.
View Article and Find Full Text PDFCancer Cell Int
December 2024
Division of Fusion Radiology Research, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea.
Background: Paclitaxel resistance and recurrence are major obstacles in ovarian cancer, which is the leading cause of death among gynecologic cancers. During cancer cell progression, cyclin-dependent kinase 1 (CDK1) drives cells through the G2 phase and into mitosis. In this study, we demonstrated that CDK1 played a crucial role in switching paclitaxel-resistant ovarian cancer cells from mitotic arrest to apoptosis following combined treatment with paclitaxel and duloxetine, an antidepressant known as a serotonin-norepinephrine reuptake inhibitor (SNRI).
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