MOZ increases p53 acetylation and premature senescence through its complex formation with PML

Abstract

Monocytic leukemia zinc finger (MOZ)/KAT6A is a MOZ, Ybf2/Sas3, Sas2, Tip60 (MYST)-type histone acetyltransferase that functions as a coactivator for acute myeloid leukemia 1 protein (AML1)-and Ets family transcription factor PU.1-dependent transcription. We previously reported that MOZ directly interacts with p53 and is essential for p53-dependent selective regulation of p21 expression. We show here that MOZ is an acetyltransferase of p53 at K120 and K382 and colocalizes with p53 in promyelocytic leukemia (PML) nuclear bodies following cellular stress. The MOZ-PML-p53 interaction enhances MOZ-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression. Moreover, we identified an Akt/ protein kinase B recognition sequence in the PML-binding domain of MOZ protein. Akt-mediated phosphorylation of MOZ at T369 has a negative effect on complex formation between PML and MOZ. As a result of PML-mediated suppression of Akt, the increased PML-MOZ interaction enhances p21 expression and induces p53-dependent premature senescence upon forced PML expression. Our research demonstrates that MOZ controls p53 acetylation and transcriptional activity via association with PML.protein modification | DNA damage T he p53 protein functions as a key regulator of pathways mediating cellular responses by inducing myriad target genes that regulate diverse cellular processes including cell-cycle arrest, apoptosis, and genomic stability (1-4). Regulation of p53 transcriptional activities is crucial for genotoxic stress because of the varieties of cellular responses that are mediated by p53, which, in some cases, can be mutually exclusive (e.g., arrest and apoptosis) (5). p53 has been detected in discrete nuclear speckles, known as promyelocytic leukemia nuclear bodies (PML-NBs), in which CREB binding protein (CBP)/p300, Tip60, and pRB are also found (6-8).PML was originally identified as a t(15, 17) chromosomal translocation partner with the retinoic acid receptor-α (RARα) in acute promyelocytic leukemia, in which fusion genes encoding the PML-RARα fusion protein are generated (9-11). The ability of PML to interact with activators such as CBP/p300 in the nuclear body suggests that PML could modulate transcription through its ability to stabilize complexes of cofactors (12, 13). Overexpression of PML, γ-irradiation of cells, or oncogenic signals such as Ras overexpression can recruit p53 into PML-NBs (14, 15). The resulting ternary p53-PML-CBP complex then promotes the acetylation of p53 and harmonically coordinates critical tumorsuppressive functions such as apoptosis, senescence, and growth arrest (16,17). Unlike bona fide coactivators such as CBP and p300, PML does not possess intrinsic histone acetylase activity. PML-mediated recruitment of both coactivators promotes p53 modification, such as acetylation and phosphorylation (16,17). Acetylation levels of p53 are known to be significantly enhanced in response to stress and are involved in p53 activation and stabilization (18,19). Given that p300 −/− mouse ...

Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53

“…This acetylation is clearly dispensable to the NIAM functions described herein, yet we wonder if that modification could also be mediated by MOZ, a Tip60 relative that specifically promotes p21 upregulation and senescence. 48 Of more immediate interest is determining how NIAM cooperates with Tip60 to activate p53 and induce p21. Does it do so by facilitating Tip60-p53 interaction on the p21 promoter, and is that associated with enhanced Tip60-mediated histone H4 acetylation and consequent relaxation of the chromatin?…”

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“…P53 mainly promotes cell cycle arrest, DNA repair and, if the damage is anbnormally wide, apoptosis. The function of p53 is to avoid DNA changes accumulation which can lead to cancerogenesis (4)(5)(6).…”

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

“…31,32 Over the course of many years, a growing number of functionally distinct proteins and enzymes were shown to be recruited into PML NBs, notably p53 and many of its regulatory enzymes. 6,23,33,34 Initially, the striking functional diversity of NB partner proteins made it difficult to assess NBs' biochemical function and physiological role. It is now generally accepted that NBs function promiscuously to fine-tune a wide spectrum of cellular activities, including stress response, senescence/apoptosis, DNA repair, anti-viral immunity and stem cell renewal.…”