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Nat Commun. 2019 Jun 28;10(1):2854. doi: 10.1038/s41467-019-10786-w.

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

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.
2
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
3
Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, 113-8421, Japan.
4
Department of Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.
5
Division of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
6
Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
7
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA. maheswaran@helix.mgh.harvard.edu.
8
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. maheswaran@helix.mgh.harvard.edu.

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.

PMID:
31253781
PMCID:
PMC6599037
DOI:
10.1038/s41467-019-10786-w
[Indexed for MEDLINE]
Free PMC Article

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