Browse > Article
http://dx.doi.org/10.14348/molcells.2015.0066

Dephosphorylation of DBC1 by Protein Phosphatase 4 Is Important for p53-Mediated Cellular Functions  

Lee, Jihye (Department of Biological Sciences, College of Science, Chonnam National University)
Adelmant, Guillaume (Department of Biological Chemistry Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute)
Marto, Jarrod A. (Department of Biological Chemistry Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute)
Lee, Dong-Hyun (Department of Biological Sciences, College of Science, Chonnam National University)
Publication Information
Molecules and Cells / v.38, no.8, 2015 , pp. 697-704 More about this Journal
Abstract
Deleted in breast cancer-1 (DBC1) contributes to the regulation of cell survival and apoptosis. Recent studies demonstrated that DBC is phosphorylated at Thr454 by ATM/ATR kinases in response to DNA damage, which is a critical event for p53 activation and apoptosis. However, how DBC1 phosphorylation is regulated has not been studied. Here we show that protein phosphatase 4 (PP4) dephosphorylates DBC1, regulating its role in DNA damage response. PP4R2, a regulatory subunit of PP4, mediates the interaction between DBC1 and PP4C, a catalytic subunit. PP4C efficiently dephosphorylates pThr454 on DBC1 in vitro, and the depletion of PP4C/PP4R2 in cells alters the kinetics of DBC1 phosphorylation and p53 activation, and increases apoptosis in response to DNA damage, which are compatible with the expression of the phosphomimetic DBC-1 mutant (T454E). These suggest that the PP4-mediated dephosphorylation of DBC1 is necessary for efficient damage responses in cells.
Keywords
deleted in breast cancer-1; depho-sphorylation; DNA damage response; protein phosphatase 4;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Chowdhury, D., Xu, X., Zhong, X., Ahmed, F., Zhong, J., Liao, J., Dykxhoorn, D. M., Weinstock, D. M., Pfeifer, G. P., and Lieberman, J. (2008). A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication. Mol. Cell 31, 33-46.   DOI   ScienceOn
2 Ciccia, A., and Elledge, S. J. (2010). The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179-204.   DOI   ScienceOn
3 Ficarro, S.B., Zhang, Y., Lu, Y., Moghimi, A.R., Askenazi, M., Hyatt, E., Smith, E.D., Boyer, L., Schlaeger, T.M., Luckey, C.J. and Marto, J.A. (2009). Improved electrospray ionization efficiency compensates for diminished chromatographic resolution and enables proteomics analysis of tyrosine signaling in embryonic stem cells. Anal. Chem. 81, 3440-3447.   DOI   ScienceOn
4 Hamaguchi, M., Meth, J.L., von Klitzing, C., Wei, W., Esposito, D., Rodgers, L., Walsh, T., Welcsh, P., King, M.C., and Wigler, M.H. (2002). DBC2, a candidate for a tumor suppressor gene involved in breast cancer. Proc. Natl. Acad. Sci. USA 99, 13647-13652.   DOI   ScienceOn
5 Ikura, T., Ogryzko, V.V., Grigoriev, M., Groisman, R., Wang, J., Horikoshi, M., Scully, R., Qin, J., and Nakatani, Y. (2000). Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463-473.   DOI   ScienceOn
6 Kim, J.E., Chen, J., and Lou, Z. (2008). DBC1 is a negative regulator of SIRT1. Nature 451, 583-586.   DOI   ScienceOn
7 Kim, J.E., Chen, J., and Lou, Z. (2009a). p30 DBC is a potential regulator of tumorigenesis. Cell Cycle 8, 2932-2935.
8 Kim, J.E., Lou, Z., and Chen, J. (2009b). Interactions between DBC1 and SIRT 1 are deregulated in breast cancer cells. Cell Cycle 8, 3784-3785.   DOI
9 Lee, D.H., and Chowdhury, D. (2011). What goes on must come off: phosphatases gate-crash the DNA damage response. Trends Biochem. Sci. 36, 569-577.   DOI   ScienceOn
10 Lee, J., and Lee, D.H. (2014). Leucine methylation of protein phosphatase PP4C at C-terminal is critical for its cellular functions. Biochem. Biophys. Res. Commun. 452, 42-47.   DOI   ScienceOn
11 Magni, M., Ruscica, V., Buscemi, G., Kim, J.E., Nachimuthu, B.T., Fontanella, E., Delia, D., and Zannini, L. (2014). Chk2 and REGgamma-dependent DBC1 regulation in DNA damage induced apoptosis. Nucleic Acids Res. 42, 13150-13160.   DOI   ScienceOn
12 Lee, D.H., Pan, Y., Kanner, S., Sung, P., Borowiec, J.A., and Chowdhury, D. (2010). A PP4 phosphatase complex dephosphorylates RPA2 to facilitate DNA repair via homologous recombination. Nat. Struct. Mol. Biol. 17, 365-372.   DOI   ScienceOn
13 Lee, D.H., Goodarzi, A.A., Adelmant, G.O., Pan, Y., Jeggo, P.A., Marto, J.A., and Chowdhury, D. (2012). Phosphoproteomic analysis reveals that PP4 dephosphorylates KAP-1 impacting the DNA damage response. EMBO J. 31, 2403-2415.   DOI
14 Lee, D.H., Acharya, S.S., Kwon, M., Drane, P., Guan, Y., Adelmant, G., Kalev, P., Shah, J., Pellman, D., Marto, J.A., et al. (2014). Dephosphorylation enables the recruitment of 53BP1 to doublestrand DNA breaks. Mol. Cell 54, 512-525.   DOI   ScienceOn
15 Matsuoka, S., Ballif, B.A., Smogorzewska, A., McDonald, E.R., 3rd, Hurov, K.E., Luo, J., Bakalarski, C.E., Zhao, Z., Solimini, N., Lerenthal, Y., et al. (2007). ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160-1166.   DOI   ScienceOn
16 Mu, J.J., Wang, Y., Luo, H., Leng, M., Zhang, J., Yang, T., Besusso, D., Jung, S.Y., and Qin, J. (2007). A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitin-proteasome system as a regulator for DNA damage checkpoints. J. Biol. Chem. 282, 17330-17334.   DOI   ScienceOn
17 Nakada, S., Chen, G.I., Gingras, A.C., and Durocher, D. (2008). PP4 is a gamma H2AX phosphatase required for recovery from the DNA damage checkpoint. EMBO Rep. 9, 1019-1026.   DOI   ScienceOn
18 Park, J.H., Lee, S.W., Yang, S.W., Yoo, H.M., Park, J.M., Seong, M.W., Ka, S.H., Oh, K.H., Jeon, Y.J., and Chung, C.H. (2014). Modification of DBC1 by SUMO2/3 is crucial for p53-mediated apoptosis in response to DNA damage. Nat. Commun. 5, 5483.   DOI   ScienceOn
19 Nakatani, Y., and Ogryzko, V. (2003). Immunoaffinity purification of mammalian protein complexes. Methods Enzymol. 370, 430-444.   DOI   ScienceOn
20 Parikh, J.R., Askenazi, M., Ficarro, S.B., Cashorali, T., Webber, J.T., Blank, N.C., Zhang, Y., and Marto, J.A. (2009). multiplierz: an extensible API based desktop environment for proteomics data analysis. BMC Bioinformatics 10, 364.   DOI   ScienceOn
21 Rozenblatt-Rosen, O., Deo, R.C., Padi, M., Adelmant, G., Calderwood, M.A., Rolland, T., Grace, M., Dricot, A., Askenazi, M., Tavares, M., et al. (2012). Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 487, 491-495.   DOI   ScienceOn
22 Smith, J., Tho, L.M., Xu, N., and Gillespie, D.A. (2010). The ATMChk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv. Cancer Res. 108, 73-112.   DOI   ScienceOn
23 Wang, B., Zhao, A., Sun, L., Zhong, X., Zhong, J., Wang, H., Cai, M., Li, J., Xu, Y., Liao, J., et al. (2008). Protein phosphatase PP4 is overexpressed in human breast and lung tumors. Cell Res. 18, 974-977.   DOI   ScienceOn
24 Wang, Q., Moore, M.J., Adelmant, G., Marto, J.A., and Silver, P.A. (2013). PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth. Genes Dev. 27, 615-626.   DOI   ScienceOn
25 Zannini, L., Buscemi, G., Kim, J.E., Fontanella, E., and Delia, D. (2012). DBC1 phosphorylation by ATM/ATR inhibits SIRT1 deacetylase in response to DNA damage. J. Mol. Cell Biol. 4, 294-303.   DOI   ScienceOn
26 Zheng, H., Yang, L., Peng, L., Izumi, V., Koomen, J., Seto, E., and Chen, J. (2013). hMOF acetylation of DBC1/CCAR2 prevents binding and inhibition of SirT1. Mol. Cell. Biol. 33, 4960-4970.   DOI   ScienceOn