title: Depletion of pre-mRNA splicing factor Cdc5L inhibits mitotic progression and triggers mitotic catastrophe.
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.
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: R
authors.initials: R
authors.lastname: Mu
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Y-B
authors.initials: YB
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: W-N
authors.initials: WN
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: A-L
authors.initials: AL
authors.lastname: Li
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: W-L
authors.initials: WL
authors.lastname: Gong
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: C-G
authors.initials: CG
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors.forename: N
authors.initials: N
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Z-H
authors.initials: ZH
authors.lastname: Sang
authors.affiliation: State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Li
mesh_terms: D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000378:metabolism*; D002470:Cell Survival; D002877:Chromosomes, Human / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D045643:DNA Repair Enzymes / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: C508357:CDC5L protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D045643:DNA Repair Enzymes; C417041:PRPF19 protein, human