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Cell. 2018 Feb 22;172(5):1007-1021.e17. doi: 10.1016/j.cell.2018.01.032.

A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02210, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 USA.
3
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cell and Developmental Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02210, USA.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cell and Developmental Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02210, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: scott_armstrong@dfci.harvard.edu.

Abstract

MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening show the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region termed the "FLOS" (functional location on SETD1A) domain is indispensable. FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The FLOS domain acts as a cyclin-K-binding site that is required for chromosomal recruitment of cyclin K and for DNA-repair-associated gene expression in S phase. These data identify a connection between the chromatin regulator SETD1A and the DNA damage response that is independent of histone methylation and suggests that targeting SETD1A and cyclin K complexes may represent a therapeutic opportunity for AML and, potentially, for other cancers.

KEYWORDS:

DNA damage response; SETD1A; cyclin K; histone methyltransferase; leukemia; transcription

PMID:
29474905
PMCID:
PMC6052445
[Available on 2019-02-22]
DOI:
10.1016/j.cell.2018.01.032

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