TY - JOUR
T1 - SETD1A protects from senescence through regulation of the mitotic gene expression program
AU - Tajima, Ken
AU - Matsuda, Satoru
AU - Yae, Toshifumi
AU - Drapkin, Benjamin J.
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
N1 - Funding Information:
We like to thank Dr. Mo Motamedi for critical reading of the manuscript. We are grateful to L. Libby for invaluable technical support. Cytometric findings reported here were performed in the MGH Department of Pathology Flow and Image Cytometry Research Core, which obtained support from the NIH Shared Instrumentation program with grants 1S10OD012027-01A1, 1S10OD016372-01, 1S10RR020936-01, and 1S10RR023440-01A1. We would like to thank Chenyue Lu (MGH Cancer Center) for helping with time-lapse imaging of cells. This work was supported by ESSCO Breast Cancer Research Fund (to S. M.), NIH Grant 2R01CA129933, the Breast Cancer Research Foundation, Howard Hughes Medical Institute, and National Foundation for Cancer Research (to D.A.H.), NIH grant R01 GM117413 (to N.D.), JSPS Overseas Research Fellowships, and JSGE Support for Young Gastroenterologists Studying in United States (S.Matsuda).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85068146822&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068146822&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10786-w
DO - 10.1038/s41467-019-10786-w
M3 - Article
C2 - 31253781
AN - SCOPUS:85068146822
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2854
ER -
