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Published on: January 26, 2018
KDM4C (GASC1) lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during
Ilana Kupershmit1, Hanan Khoury-Haddad1, Samah W Awwad1
1Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel.
Abstract:
Various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis. On this basis, it was hypothesized that dysregulated expression of KDM4A-D family promotes chromosomal instabilities by largely unknown mechanisms. Here, we show that unlike KDM4A-B, KDM4C is associated with chromatin during mitosis. This association is accompanied by a decrease in the mitotic levels of H3K9me3. We also show that the C-terminal region, containing the Tudor domains of KDM4C, is essential for its association with mitotic chromatin. More specifically, we show that R919 residue on the proximal Tudor domain of KDM4C is critical for its association with chromatin during mitosis. Interestingly, we demonstrate that depletion or overexpression of KDM4C, but not KDM4B, leads to over 3-fold increase in the frequency of abnormal mitotic cells showing either misaligned chromosomes at metaphase, anaphase-telophase lagging chromosomes or anaphase-telophase bridges. Furthermore, overexpression of KDM4C demethylase-dead mutant has no detectable effect on mitotic chromosome segregation. Altogether, our findings implicate KDM4C demethylase activity in regulating the fidelity of mitotic chromosome segregation by a yet unknown mechanism.
Insights
Lysine demethylase KDM4C regulates mitotic chromosome segregation. Its activity is crucial for preventing chromosomal instabilities and ensuring accurate cell division in cancer.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Members of the KDM4 family (KDM4A-D) are implicated in carcinogenesis due to their role in demethylating H3K9 and H3K36.
- Dysregulated KDM4A-D expression is hypothesized to promote chromosomal instability through largely unknown mechanisms.
Purpose of the Study:
- To investigate the role of KDM4C in mitotic chromosome segregation and its potential contribution to chromosomal instability.
Main Methods:
- Immunofluorescence to detect KDM4C association with mitotic chromatin.
- Western blotting to assess H3K9me3 levels during mitosis.
- Depletion and overexpression studies of KDM4C and KDM4B, including a demethylase-dead mutant.
- Analysis of mitotic cell abnormalities (chromosome misalignment, lagging chromosomes, bridges).
Main Results:
- KDM4C, unlike KDM4A-B, associates with mitotic chromatin, correlating with decreased H3K9me3 levels.
- The C-terminal Tudor domains of KDM4C, specifically residue R919, are essential for mitotic chromatin association.
- Depletion or overexpression of KDM4C significantly increases mitotic errors (over 3-fold), while KDM4B does not.
- A demethylase-dead KDM4C mutant does not affect mitotic chromosome segregation fidelity.
Conclusions:
- KDM4C's demethylase activity is critical for regulating the fidelity of mitotic chromosome segregation.
- KDM4C plays a key role in maintaining chromosomal stability during mitosis, independent of KDM4B.
- The findings suggest a novel mechanism by which KDM4C activity impacts cancer development through mitotic regulation.
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