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
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
Cell
Date: Dec. 22, 2017
PubMed ID: 29474905
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