Title:
A non-catalytic function of histone methyltransferase regulates DNA damage response

 

Speaker:
Takayuki Hoshii, PhD
Assistant Professor
Department of Innovative Medicine, Graduate School of Medicine, Chiba University

 

Abstract:
MLL family member proteins (MLL1-4, SETD1A/B) are known histone H3K4 methyltransferases. H3K4 methylation is associated with active transcription and many studies indicate biological roles for H3K4 methylation in development as well as cancer. Genetic deletion experiments of H3K4 methyltransferases revealed the indispensable roles of MLL family proteins in various forms of cancer such as leukemia. MLL1 is also known as a driver oncogene in infant leukemia and the MLL-rearranged (MLL-r) allele is associated with poor prognosis. We assessed MLL/SET proteins and found that SETD1A is required for survival of MLL-r 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. In addition to the cyclin K-interaction, we also identified a novel protein interaction of SETD1A that is important for the leukemia progression. Here we will share a different aspect of SETD1A function in DNA damage response.

 

References:
Hoshii T, Cifani P, Feng Z, Huang CH, Koche R, Chen CW, Delaney CD, Lowe SW, Kentsis A, Armstrong SA. A non-catalytic function of SETD1A regulates Cyclin-K and the DNA damage response. Cell. 2018 Feb 22;172(5):1007-1021.e17. doi: 10.1016/j.cell.2018.01.032.