| First Author | Hoshii T | Year | 2018 |
| Journal | Cell | Volume | 172 |
| Issue | 5 | Pages | 1007-1021.e17 |
| PubMed ID | 29474905 | Mgi Jnum | J:259105 |
| Mgi Id | MGI:6120279 | Doi | 10.1016/j.cell.2018.01.032 |
| Citation | Hoshii T, et al. (2018) A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. Cell 172(5):1007-1021.e17 |
| abstractText | 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. |
