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 |
| PMCID: | PMC6052445 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 April 2018 -- Source: Scopus |
