Journal
CELL
Volume 172, Issue 5, Pages 1007-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.01.032
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Funding
- Kanae Foundation forthe Promotion of Medical Science
- JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, JAPAN
- NCI [CA190261, CA204396, P30 CA008748, CA066996, CA140575]
- Leukemia and Lymphoma Society
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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.
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