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

Hoshii, Takayuki; Cifani, Paolo; Feng, Zhaohui; Huang, Chun-Hao; Koche, Richard; Chen, Chun-Wei; Delaney, Christopher D; Lowe, Scott W; Kentsis, Alex; Armstrong, Scott A.
Cell; 172(5): 1007-1021.e17, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474905
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.