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

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10786-w

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