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DNA damage Role of SUMO in p53 regulation

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DNA damage Role of SUMO in p53 regulation

Role of SUMO in p53 regulation

Tumor suppressor p53 acts in many tumor types and induces growth arrest orapoptosis depending on the physiological circumstances and cell type. This protein isinvolved in the cell cycle regulation as a trans-activator. Abundance and activity of thetumor suppressor p53 are regulated by many different posttranslationalmodifications. Covalent modification with the small ubiquitin- related protein (SUMO) isa one of these paths.

SUMO is a protein moiety that is ligated to lysine residues in a variety of targetproteins. The addition of SUMO can modulate the ability of proteins to interact withtheir partners, alter their patterns of subcellular localization and control theirstability. Four different ubiquitous SUMO-related proteins have been identified inmammalian cells [1]. It was shown that one of them, SUMO-1,participates in p53 regulation [1].

In response to ionizing or UV-irradiation, c ell cycle checkpoint kinase 2 (Chk2 ) phosphorylates of p53 on Ser-20 [2]. It stimulates, inturn, SUMO-modification (sumoylation) of p53 [3].

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 ( SAE1and Uba2 ). Subsequently, SUMO-1 is transferred to E2-conjugating enzymeE2I [4],[5] according to others, the effect is inhibition [6] or noeffect [7]. It is shown that PIAS proteins strongly repressthe transcriptional activity of p53 [6].

Regulation of p53 by sumoylation is probably mediated by p53 regulatorssuch as ubiquitin-protein ligase E3 MDM2, promyelocytic leukemia proteinPML, death-associated protein 6 DAXX).

MDM2 is an ubiquitin-protein ligase E3. It ubiquitinates p53 and thuspromotes proteasomal degradation of p53 [8]. On the other hand, the mdm2gene is a direct target for binding and transcriptional activation by p53 [9]. When DNA in a cell is damaged by genotoxic stress, p53 isphosphorylated at its amino terminus by kinases. MDM2 cannot bind andubiquitinylate phosphorylated p53.

MDM2 is activated by sumoylation with participate SAE1/2, E2Iand some E3 ligases. E2I - MDM2 interaction may be repressed byUV-irradiation [10]. Finally, MDM2 is sumoylated during nucleartranslocation by E3 ligase - RanBP2 (nuclear pore protein) and then furthersumoylated once in the nucleus by other E3 ligases PIAS (nucleoplasmic proteins)[10].

PML is a phosphoprotein that localizes to nuclear bodies (NB) where itfunctions as a transcription factor and tumor suppressor. PML sumolation led torecruitment p53 and p53-activator CBP NB [11]. CBP andco-activator p300 in turn activates p53 by acetylation [12],[13]. 

Moreover, SUMO-1 -modified PML stimulates recruitment DAXX intoNB [14]. DAXX functions as a transcriptional repressor of p53,which competes with transcriptional activator PML [15].