A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4.
ASC-2, a multifunctional coactivator, forms a 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 MLL3 and MLL4, targeted inactivation of the MLL3 H3K4-methylation activity in mice is found to result in ureter epithelial tumors. Interestingly, this phenotype is exacerbated in a p53(+/-) background and the tumorigenic cells are heavily immunostained for gammaH2AX, indicating a contribution of MLL3 to the DNA damage response pathway through p53. Consistent with the in vivo observations, and the demonstration of a direct interaction between p53 and ASCOM, cell-based assays have revealed that ASCOM, through ASC-2 and MLL3/4, acts as a p53 coactivator and is required for H3K4-trimethyation and expression of endogenous p53-target genes in response to the DNA damaging agent doxorubicin. In support of redundant functions for MLL3 and MLL4 for some events, siRNA-mediated down-regulation of both MLL3 and MLL4 is required to suppress doxorubicin-inducible expression of several p53-target genes. Importantly, this study identifies a specific H3K4 methytransferase complex, ASCOM, as a physiologically relevant coactivator for p53 and implicates ASCOM in the p53 tumor suppression pathway in vivo.
Lee
Jeongkyung
J
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Kim
Dae-Hwan
DH
Lee
Seunghee
S
Yang
Qi-Heng
QH
Lee
Dong Kee
DK
Lee
Soo-Kyung
SK
Roeder
Robert G
RG
Lee
Jae W
JW
D000818:Animals; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004789:Enzyme Activation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D056918:Nuclear Receptor Coactivators; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014516:Ureteral Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins
D011495:Histone-Lysine N-Methyltransferase; D047908:Intracellular Signaling Peptides and Proteins; D056918:Nuclear Receptor Coactivators; D016159:Tumor Suppressor Protein p53; C405683:Ncoa6 protein, mouse; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins; C516439:MLL4 protein, mouse