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

Author: Hoshii, T.; Cifani, P.; Feng, Z.; Huang, C.-H.; Koche, R.; Chen, C.-W.; Delaney, C.D.; Lowe, S.W.; Kentsis, A.; Armstrong, S.A.

Description: 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.

Subject Headings: DNA damage response; Setd1a; cyclin K; histone methyltransferase; leukemia; transcription

Subject headings:

Publication year: 2018

Journal or book title: Cell

Volume: 172

Issue: 5

Pages: 1007-1021.e17

Find the full text : https://www.sciencedirect.com/science/article/pii/S0092867418301090

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Type: Journal Article

Serial number: 2289