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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Jeongkyung
J
Lee
Dae-Hwan
DH
Kim
Seunghee
S
Lee
Qi-Heng
QH
Yang
Dong Kee
DK
Lee
Soo-Kyung
SK
Lee
Robert G
RG
Roeder
Jae W
JW
Lee
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