SETD1A protects from senescence through regulation of the mitotic gene expression program

Ken Tajima; Satoru Matsuda; Toshifumi Yae; Benjamin J. Drapkin; Robert Morris; Myriam Boukhali; Kira Niederhoffer; Valentine Comaills; Taronish Dubash; Linda Nieman; Hongshan Guo; Neelima K.C. Magnus; Nick Dyson; Toshihiro Shioda; Wilhelm Haas; Daniel A. Haber; Shyamala Maheswaran

doi:10.1038/s41467-019-10786-w

SETD1A protects from senescence through regulation of the mitotic gene expression program

Ken Tajima, Satoru Matsuda, Toshifumi Yae, Benjamin J. Drapkin, Robert Morris, Myriam Boukhali, Kira Niederhoffer, Valentine Comaills, Taronish Dubash, Linda Nieman, Hongshan Guo, Neelima K.C. Magnus, Nick Dyson, Toshihiro Shioda, Wilhelm Haas, Daniel A. Haber, Shyamala Maheswaran

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

SETD1A, a Set1/COMPASS family member maintaining histone-H3-lysine-4 (H3K4) methylation on transcriptionally active promoters, is overexpressed in breast cancer. Here, we show that SETD1A supports mitotic processes and consequentially, its knockdown induces senescence. SETD1A, through promoter H3K4 methylation, regulates several genes orchestrating mitosis and DNA-damage responses, and its depletion causes chromosome misalignment and segregation defects. Cell cycle arrest in SETD1A knockdown senescent cells is independent of mutations in p53, RB and p16, known senescence mediators; instead, it is sustained through transcriptional suppression of SKP2, which degrades p27 and p21. Rare cells escaping senescence by restoring SKP2 expression display genomic instability. In > 200 cancer cell lines and in primary circulating tumor cells, SETD1A expression correlates with genes promoting mitosis and cell cycle suggesting a broad role in suppressing senescence induced by aberrant mitosis. Thus, SETD1A is essential to maintain mitosis and proliferation and its suppression unleashes the tumor suppressive effects of senescence.

Original language	English (US)
Article number	2854
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10786-w
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Tajima, K., Matsuda, S., Yae, T., Drapkin, B. J., Morris, R., Boukhali, M., Niederhoffer, K., Comaills, V., Dubash, T., Nieman, L., Guo, H., Magnus, N. K. C., Dyson, N., Shioda, T., Haas, W., Haber, D. A., & Maheswaran, S. (2019). SETD1A protects from senescence through regulation of the mitotic gene expression program. Nature communications, 10(1), Article 2854. https://doi.org/10.1038/s41467-019-10786-w

Tajima, K, Matsuda, S, Yae, T, Drapkin, BJ, Morris, R, Boukhali, M, Niederhoffer, K, Comaills, V, Dubash, T, Nieman, L, Guo, H, Magnus, NKC, Dyson, N, Shioda, T, Haas, W, Haber, DA & Maheswaran, S 2019, 'SETD1A protects from senescence through regulation of the mitotic gene expression program', Nature communications, vol. 10, no. 1, 2854. https://doi.org/10.1038/s41467-019-10786-w

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abstract = "SETD1A, a Set1/COMPASS family member maintaining histone-H3-lysine-4 (H3K4) methylation on transcriptionally active promoters, is overexpressed in breast cancer. Here, we show that SETD1A supports mitotic processes and consequentially, its knockdown induces senescence. SETD1A, through promoter H3K4 methylation, regulates several genes orchestrating mitosis and DNA-damage responses, and its depletion causes chromosome misalignment and segregation defects. Cell cycle arrest in SETD1A knockdown senescent cells is independent of mutations in p53, RB and p16, known senescence mediators; instead, it is sustained through transcriptional suppression of SKP2, which degrades p27 and p21. Rare cells escaping senescence by restoring SKP2 expression display genomic instability. In > 200 cancer cell lines and in primary circulating tumor cells, SETD1A expression correlates with genes promoting mitosis and cell cycle suggesting a broad role in suppressing senescence induced by aberrant mitosis. Thus, SETD1A is essential to maintain mitosis and proliferation and its suppression unleashes the tumor suppressive effects of senescence.",

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AU - Tajima, Ken

AU - Matsuda, Satoru

AU - Yae, Toshifumi

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AU - Morris, Robert

AU - Boukhali, Myriam

AU - Niederhoffer, Kira

AU - Comaills, Valentine

AU - Dubash, Taronish

AU - Nieman, Linda

AU - Guo, Hongshan

AU - Magnus, Neelima K.C.

AU - Dyson, Nick

AU - Shioda, Toshihiro

AU - Haas, Wilhelm

AU - Haber, Daniel A.

AU - Maheswaran, Shyamala

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N2 - SETD1A, a Set1/COMPASS family member maintaining histone-H3-lysine-4 (H3K4) methylation on transcriptionally active promoters, is overexpressed in breast cancer. Here, we show that SETD1A supports mitotic processes and consequentially, its knockdown induces senescence. SETD1A, through promoter H3K4 methylation, regulates several genes orchestrating mitosis and DNA-damage responses, and its depletion causes chromosome misalignment and segregation defects. Cell cycle arrest in SETD1A knockdown senescent cells is independent of mutations in p53, RB and p16, known senescence mediators; instead, it is sustained through transcriptional suppression of SKP2, which degrades p27 and p21. Rare cells escaping senescence by restoring SKP2 expression display genomic instability. In > 200 cancer cell lines and in primary circulating tumor cells, SETD1A expression correlates with genes promoting mitosis and cell cycle suggesting a broad role in suppressing senescence induced by aberrant mitosis. Thus, SETD1A is essential to maintain mitosis and proliferation and its suppression unleashes the tumor suppressive effects of senescence.

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SETD1A protects from senescence through regulation of the mitotic gene expression program

Abstract

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