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

Author

Listed:
  • Ken Tajima

    (Harvard Medical School
    Harvard Medical School
    Juntendo University School of Medicine)

  • Satoru Matsuda

    (Harvard Medical School
    Harvard Medical School
    Keio University School of Medicine)

  • Toshifumi Yae

    (Harvard Medical School
    Harvard Medical School)

  • Benjamin J. Drapkin

    (Harvard Medical School
    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
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Shyamala Maheswaran

    (Harvard Medical School
    Harvard Medical School)

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.

Suggested Citation

  • 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, 2019. "SETD1A protects from senescence through regulation of the mitotic gene expression program," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10786-w
    DOI: 10.1038/s41467-019-10786-w
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    Cited by:

    1. Yuzhou Chang & Jixin Liu & Yi Jiang & Anjun Ma & Yao Yu Yeo & Qi Guo & Megan McNutt & Jordan E. Krull & Scott J. Rodig & Dan H. Barouch & Garry P. Nolan & Dong Xu & Sizun Jiang & Zihai Li & Bingqiang , 2024. "Graph Fourier transform for spatial omics representation and analyses of complex organs," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Samuel Hume & Claudia P. Grou & Pauline Lascaux & Vincenzo D’Angiolella & Arnaud J. Legrand & Kristijan Ramadan & Grigory L. Dianov, 2021. "The NUCKS1-SKP2-p21/p27 axis controls S phase entry," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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