A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4

摘要: ASC-2, a multifunctional coactivator, forms steady-state complex, named ASCOM (for ASC-2 COMplex), that contains the histone H3-lysine-4 (H3K4)-methyltransferase MLL3 or its paralogue MLL4. Somewhat surprisingly, given prior indications of redundancy between and MLL4, targeted inactivation H3K4-methylation activity in mice is found to result ureter epithelial tumors. Interestingly, this phenotype exacerbated p53+/− background tumorigenic cells are heavily immunostained for γH2AX, indicating contribution DNA damage response pathway through p53. Consistent with vivo observations, demonstration direct interaction p53 ASCOM, cell-based assays have revealed MLL3/4, acts as coactivator required H3K4-trimethyation expression endogenous p53-target genes damaging agent doxorubicin. In support redundant functions MLL4 some events, siRNA-mediated down-regulation both suppress doxorubicin-inducible several genes. Importantly, study identifies specific H3K4 methytransferase physiologically relevant implicates tumor suppression vivo.