Depletion of pre-mRNA splicing factor Cdc5L inhibits mitotic progression and triggers mitotic catastrophe
1State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
Abstract:
Disturbing mitotic progression via targeted anti-mitotic therapy is an attractive strategy for cancer treatment. Therefore, the exploration and elucidation of molecular targets and pathways in mitosis are critical for the development of anti-mitotic drugs. Here, we show that cell division cycle 5-like (Cdc5L), a pre-mRNA splicing factor, is a regulator of mitotic progression. Depletion of Cdc5L causes dramatic mitotic arrest, chromosome misalignments and sustained activation of spindle assembly checkpoint, eventually leading to mitotic catastrophe. Moreover, these defects result from severe impairment of kinetochore-microtubule attachment and serious DNA damage. Genome-wide gene expression analysis reveals that Cdc5L modulates the expression of a set of genes involved in the mitosis and the DNA damage response. We further found that the pre-mRNA splicing efficiency of these genes were impaired when Cdc5L was knocked down. Interestingly, Cdc5L is highly expressed in cervical tumors and osteosarcoma. Finally, we demonstrate that downregulation of Cdc5L decreases the cell viability of related tumor cells. These results suggest that Cdc5L is a key regulator of mitotic progression and highlight the potential of Cdc5L as a target for cancer therapy.
Insights
Cell division cycle 5-like (Cdc5L), a splicing factor, regulates mitosis. Depleting Cdc5L causes mitotic arrest and DNA damage, suggesting its potential as an anti-cancer drug target.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Targeting mitotic progression is a key anti-cancer strategy.
- Identifying novel molecular targets in mitosis is crucial for drug development.
Purpose of the Study:
- To investigate the role of cell division cycle 5-like (Cdc5L) in mitotic progression.
- To explore Cdc5L as a potential therapeutic target for cancer.
Main Methods:
- Depletion of Cdc5L using knockdown techniques.
- Analysis of mitotic progression, chromosome alignment, and spindle assembly checkpoint.
- Assessment of kinetochore-microtubule attachment and DNA damage.
- Genome-wide gene expression analysis.
- Investigation of pre-mRNA splicing efficiency.
Main Results:
- Cdc5L depletion induced mitotic arrest, chromosome misalignment, and sustained spindle assembly checkpoint activation.
- Defects were linked to impaired kinetochore-microtubule attachment and DNA damage.
- Cdc5L knockdown affected the expression and splicing of mitosis and DNA damage response genes.
- Cdc5L is highly expressed in cervical tumors and osteosarcoma.
- Downregulation of Cdc5L reduced tumor cell viability.
Conclusions:
- Cdc5L is a critical regulator of mitotic progression.
- Cdc5L plays a role in maintaining genomic stability by influencing gene expression and splicing.
- Cdc5L represents a promising therapeutic target for cervical and osteosarcoma treatment.
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