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.