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

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.
Mesh Terms:
Animals, Biocatalysis, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cyclins, DNA Damage, Fanconi Anemia Complementation Group D2 Protein, Gene Expression Regulation, Leukemic, Gene Knockdown Techniques, Histone-Lysine N-Methyltransferase, Histones, Humans, Leukemia, Myeloid, Acute, Mice, Protein Binding, Protein Domains, Protein Stability, Transcription, Genetic
Date: Dec. 22, 2017
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