A non-catalytic function of SETD1A regulates cyclin K and the DNA damage response Journal Article

Authors: 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.
Article Title: A non-catalytic function of SETD1A regulates cyclin K and the DNA damage response
Abstract: 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. Independent of its enzymatic activity, H3K4 methyltransferase SETD1A promotes leukemic cell survival by regulating DNA damage response. © 2018 Elsevier Inc.
Keywords: controlled study; leukemia; unclassified drug; human cell; nonhuman; protein domain; mouse; animal tissue; dna damage; cell survival; cell cycle s phase; complex formation; dna repair; apoptosis; cell growth; protein protein interaction; animal experiment; animal model; protein p53; gene expression regulation; histone methyltransferase; histone h3; tumor protein; transcription; dna damage response; binding site; mutagenesis; regulator protein; histone methylation; acute myeloid leukemia; human; male; female; priority journal; article; crispr-cas9 system; acute myeloid leukemia cell line; cyclin k; setd1a; setd1a protein
Journal Title: Cell
Volume: 172
Issue: 5
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2018-02-22
Start Page: 1007
End Page: 1021.e17
Language: English
DOI: 10.1016/j.cell.2018.01.032
PROVIDER: scopus
PUBMED: 29474905
Notes: Article -- Export Date: 2 April 2018 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Scott W Lowe
    147 Lowe
  2. Scott Allen Armstrong
    108 Armstrong
  3. Chun-Wei Chen
    19 Chen
  4. Alex   Kentsis
    50 Kentsis
  5. Chun-Hao   Huang
    18 Huang
  6. Paolo   Cifani
    17 Cifani
  7. Zhaohui   Feng
    6 Feng
  8. Takayuki   Hoshii
    8 Hoshii