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DNA damage_Role of SUMO in p53 regulation
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Role of SUMO in p53 regulation
Tumor suppressor p53 acts in many tumor types and induces growth arrest or apoptosis depending on the physiological circumstances and cell type. This protein is involved in the cell cycle regulation as a trans-activator. Abundance and activity of the tumor suppressor p53 are regulated by many different posttranslational modifications. Covalent modification with the small ubiquitin- related protein (SUMO) is a one of these paths.
SUMO is a protein moiety that is ligated to lysine residues in a variety of target proteins. The addition of SUMO can modulate the ability of proteins to interact with their partners, alter their patterns of subcellular localization and control their stability. Four different ubiquitous SUMO-related proteins have been identified in mammalian cells . It was shown that one of them, SUMO-1, participates in p53 regulation .
SUMO-1 is activated by the specific activity of E1 ligase ( SAE1/2 ), which is a heterodimer comprising SUMO-1 activating enzyme subunits 1 and 2 ( SAE1 and Uba2 ). Subsequently, SUMO-1 is transferred to E2-conjugating enzyme E2I . Further, E2I transfers SUMO-1 to the substrate p53. Data on influence of sumoylation on activity p53 is contradictory. According to some studies, that sumoylation activates p53 ,  according to others, the effect is inhibition  or no effect .
It is shown that E3 ligases may participate in sumoylation. RING finger E3 ligases PIAS are thought to facilitate direct transfer of SUMO-1 from E2I to the p53 . It is shown that PIAS proteins strongly repress the transcriptional activity of p53 .
Regulation of p53 by sumoylation is probably mediated by p53 regulators such as ubiquitin-protein ligase E3 MDM2, promyelocytic leukemia protein PML, death-associated protein 6 DAXX).
MDM2 is an ubiquitin-protein ligase E3. It ubiquitinates p53 and thus promotes proteasomal degradation of p53  and/or blocks the interactions between p53 and p53-activators (CREB-binding protein CBP and E1A-binding protein p300 ) . On the other hand, the mdm2 gene is a direct target for binding and transcriptional activation by p53 . When DNA in a cell is damaged by genotoxic stress, p53 is phosphorylated at its amino terminus by kinases. MDM2 cannot bind and ubiquitinylate phosphorylated p53.
MDM2 is activated by sumoylation with participate SAE1/2, E2I and some E3 ligases. E2I - MDM2 interaction may be repressed by UV-irradiation . Finally, MDM2 is sumoylated during nuclear translocation by E3 ligase - RanBP2 (nuclear pore protein) and then further sumoylated once in the nucleus by other E3 ligases PIAS (nucleoplasmic proteins) .
PML is a phosphoprotein that localizes to nuclear bodies (NB) where it functions as a transcription factor and tumor suppressor. PML sumolation led to recruitment p53 and p53-activator CBP NB . CBP and co-activator p300 in turn activates p53 by acetylation , .
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