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 [1]. It was shown that one of them, SUMO-1, participates in p53 regulation [1].

In response to ionizing or UV-irradiation, cell cycle checkpoint kinase 2 (Chk2) phosphorylates of p53 on Ser-20 [2]. It stimulates, in turn, 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 (SAE1 and Uba2). Subsequently, SUMO-1 is transferred to E2-conjugating enzyme E2I [4]. 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[5], [6] according to others, the effect is inhibition [7] or no effect [8].

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 [4]. It is shown that PIAS proteins strongly repress the transcriptional activity of p53 [7].

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 [9] and/or blocks the interactions between p53 and p53-activators (CREB-binding protein CBP and E1A-binding protein p300) [10]. On the other hand, the mdm2 gene is a direct target for binding and transcriptional activation by p53 [11]. 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 [12]. 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) [13].

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 [14]. CBP and co-activator p300 in turn activates p53 by acetylation [15], [16].

Moreover, SUMO-1-modified PML stimulates recruitment DAXX into NB [17]. DAXX functions as a transcriptional repressor of p53, which competes with transcriptional activator PML [18].

References:

  1. Melchior F, Hengst L
    SUMO-1 and p53. Cell cycle (Georgetown, Tex.) 2002 Jul-Aug;1(4):245-9
  2. Saito S, Goodarzi AA, Higashimoto Y, Noda Y, Lees-Miller SP, Appella E, Anderson CW
    ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation. The Journal of biological chemistry 2002 Apr 12;277(15):12491-4
  3. Lin JY, Ohshima T, Shimotohno K
    Association of Ubc9, an E2 ligase for SUMO conjugation, with p53 is regulated by phosphorylation of p53. FEBS letters 2004 Aug 27;573(1-3):15-8
  4. Kotaja N, Karvonen U, Janne OA, Palvimo JJ
    PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Molecular and cellular biology 2002 Jul;22(14):5222-34
  5. Rodriguez MS, Desterro JM, Lain S, Midgley CA, Lane DP, Hay RT
    SUMO-1 modification activates the transcriptional response of p53. The EMBO journal 1999 Nov 15;18(22):6455-61
  6. Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A
    c-Jun and p53 activity is modulated by SUMO-1 modification. The Journal of biological chemistry 2000 May 5;275(18):13321-9
  7. Schmidt D, Muller S
    Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proceedings of the National Academy of Sciences of the United States of America 2002 Mar 5;99(5):2872-7
  8. Kwek SS, Derry J, Tyner AL, Shen Z, Gudkov AV
    Functional analysis and intracellular localization of p53 modified by SUMO-1. Oncogene 2001 May 3;20(20):2587-99
  9. Asher G, Shaul Y
    p53 proteasomal degradation: poly-ubiquitination is not the whole story. Cell cycle (Georgetown, Tex.) 2005 Aug;4(8):1015-8
  10. Wadgaonkar R, Collins T
    Murine double minute (MDM2) blocks p53-coactivator interaction, a new mechanism for inhibition of p53-dependent gene expression. The Journal of biological chemistry 1999 May 14;274(20):13760-7
  11. Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Leal JF, Maya R, Moas M, Seger R, Taya Y, Ben-Ze'Ev A
    Regulation of p53: intricate loops and delicate balances. Annals of the New York Academy of Sciences 2002 Nov;973:374-83
  12. Buschmann T, Lerner D, Lee CG, Ronai Z
    The Mdm-2 amino terminus is required for Mdm2 binding and SUMO-1 conjugation by the E2 SUMO-1 conjugating enzyme Ubc9. The Journal of biological chemistry 2001 Nov 2;276(44):40389-95
  13. Miyauchi Y, Yogosawa S, Honda R, Nishida T, Yasuda H
    Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes. The Journal of biological chemistry 2002 Dec 20;277(51):50131-6
  14. Fogal V, Gostissa M, Sandy P, Zacchi P, Sternsdorf T, Jensen K, Pandolfi PP, Will H, Schneider C, Del Sal G
    Regulation of p53 activity in nuclear bodies by a specific PML isoform. The EMBO journal 2000 Nov 15;19(22):6185-95
  15. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP, Pelicci PG
    PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000 Jul 13;406(6792):207-10
  16. Grossman SR
    p300/CBP/p53 interaction and regulation of the p53 response. European journal of biochemistry / FEBS 2001 May;268(10):2773-8
  17. Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T, Yeh ET, Strauss JF 3rd, Maul GG
    PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. The Journal of cell biology 1999 Oct 18;147(2):221-34
  18. Kim EJ, Park JS, Um SJ
    Identification of Daxx interacting with p73, one of the p53 family, and its regulation of p53 activity by competitive interaction with PML. Nucleic acids research 2003 Sep 15;31(18):5356-67

  1. Melchior F, Hengst L
    SUMO-1 and p53. Cell cycle (Georgetown, Tex.) 2002 Jul-Aug;1(4):245-9
  2. Saito S, Goodarzi AA, Higashimoto Y, Noda Y, Lees-Miller SP, Appella E, Anderson CW
    ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation. The Journal of biological chemistry 2002 Apr 12;277(15):12491-4
  3. Lin JY, Ohshima T, Shimotohno K
    Association of Ubc9, an E2 ligase for SUMO conjugation, with p53 is regulated by phosphorylation of p53. FEBS letters 2004 Aug 27;573(1-3):15-8
  4. Kotaja N, Karvonen U, Janne OA, Palvimo JJ
    PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Molecular and cellular biology 2002 Jul;22(14):5222-34
  5. Rodriguez MS, Desterro JM, Lain S, Midgley CA, Lane DP, Hay RT
    SUMO-1 modification activates the transcriptional response of p53. The EMBO journal 1999 Nov 15;18(22):6455-61
  6. Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A
    c-Jun and p53 activity is modulated by SUMO-1 modification. The Journal of biological chemistry 2000 May 5;275(18):13321-9
  7. Schmidt D, Muller S
    Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proceedings of the National Academy of Sciences of the United States of America 2002 Mar 5;99(5):2872-7
  8. Kwek SS, Derry J, Tyner AL, Shen Z, Gudkov AV
    Functional analysis and intracellular localization of p53 modified by SUMO-1. Oncogene 2001 May 3;20(20):2587-99
  9. Asher G, Shaul Y
    p53 proteasomal degradation: poly-ubiquitination is not the whole story. Cell cycle (Georgetown, Tex.) 2005 Aug;4(8):1015-8
  10. Wadgaonkar R, Collins T
    Murine double minute (MDM2) blocks p53-coactivator interaction, a new mechanism for inhibition of p53-dependent gene expression. The Journal of biological chemistry 1999 May 14;274(20):13760-7
  11. Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Leal JF, Maya R, Moas M, Seger R, Taya Y, Ben-Ze'Ev A
    Regulation of p53: intricate loops and delicate balances. Annals of the New York Academy of Sciences 2002 Nov;973:374-83
  12. Buschmann T, Lerner D, Lee CG, Ronai Z
    The Mdm-2 amino terminus is required for Mdm2 binding and SUMO-1 conjugation by the E2 SUMO-1 conjugating enzyme Ubc9. The Journal of biological chemistry 2001 Nov 2;276(44):40389-95
  13. Miyauchi Y, Yogosawa S, Honda R, Nishida T, Yasuda H
    Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes. The Journal of biological chemistry 2002 Dec 20;277(51):50131-6
  14. Fogal V, Gostissa M, Sandy P, Zacchi P, Sternsdorf T, Jensen K, Pandolfi PP, Will H, Schneider C, Del Sal G
    Regulation of p53 activity in nuclear bodies by a specific PML isoform. The EMBO journal 2000 Nov 15;19(22):6185-95
  15. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP, Pelicci PG
    PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000 Jul 13;406(6792):207-10
  16. Grossman SR
    p300/CBP/p53 interaction and regulation of the p53 response. European journal of biochemistry / FEBS 2001 May;268(10):2773-8
  17. Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T, Yeh ET, Strauss JF 3rd, Maul GG
    PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. The Journal of cell biology 1999 Oct 18;147(2):221-34
  18. Kim EJ, Park JS, Um SJ
    Identification of Daxx interacting with p73, one of the p53 family, and its regulation of p53 activity by competitive interaction with PML. Nucleic acids research 2003 Sep 15;31(18):5356-67

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