A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response
2018
Summary 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-
Cas9domain screening show the enzymatic
SET domainis not necessary for AML cell survival but that a newly identified region termed the "
FLOS" (functional location on SETD1A) domain is indispensable.
FLOSdisruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The
FLOSdomain acts as a
cyclin-K-binding site that is required for chromosomal recruitment of
cyclinK 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 methylationand suggests that targeting SETD1A and
cyclin
K complexesmay represent a therapeutic opportunity for AML and, potentially, for other cancers.
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