Skip to main content
SpringerLink
Log in

Sumoylation in Craniofacial Disorders

  • Chapter
  • First Online:
SUMO Regulation of Cellular Processes

Abstract

Craniofacial development requires a complex series of coordinated and finely tuned events to take place, during a relatively short time frame. These events are set in motion by switching on and off transcriptional cascades that involve the use of numerous signalling pathways and a multitude of factors that act at the site of gene transcription. It is now well known that amidst the subtlety of this process lies the intricate world of protein modification. Most recently, the post-translational addition of the small ubiqiutin-like modifier, SUMO, has been implicated in this process. Many proteins that are required for formation of various structures in the embryonic head and face adapt specific functions with this modification. In fact, the main phenotype detected for SUMO1 disruption manifests as the common birth defect cleft lip and palate. In this chapter we discuss the role of SUMO1 in craniofacial development, with emphasis on orofacial clefts. We suggest that these defects can be a sensitive indication of down regulated SUMO modification at a critical stage during embryogenesis. As well as specific mutations affecting the ability of particular proteins to be sumoylated, non-genetic events may have the effect of down-regulating the SUMO pathway to give the same result. Enzymes regulating the SUMO pathway may become important therapeutic targets in the preventative and treatment therapies for craniofacial defects in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J. and Petit, C., 1997, A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat. Genet. 15, 157–164.

    Article  PubMed  CAS  Google Scholar 

  • Alkuraya, F. S., Saadi, I., Lund, J. J., Turbe-Doan, A., Morton, C. C. and Maas, R. L., 2006, SUMO1 haploinsufficiency leads to cleft lip and palate. Science 313, 1751.

    Article  PubMed  Google Scholar 

  • Andreou, A. M., Pauws, E., Jones, M. C., Singh, M. K., Bussen, M., Doudney, K., Moore, G. E., Kispert, A., Brosens, J. J. and Stanier, P., 2007, TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. Am. J. Hum. Genet. 81, 700–712.

    Article  PubMed  CAS  Google Scholar 

  • Bossis, G. and Melchior, F., 2006, Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol. Cell 21, 349–357.

    Article  PubMed  CAS  Google Scholar 

  • Braybrook, C., Doudney, K., Marçano, A. C., Arnason, A., Bjornsson, A., Patton, M. A., Goodfellow, P. J., Moore, G. E. and Stanier, P., 2001, The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia. Nat. Genet. 29, 179–183

    Article  PubMed  CAS  Google Scholar 

  • Chakravarti, A. and Little, P., 2003, Nature, nurture and human disease. Nature 421, 412–414.

    Article  PubMed  Google Scholar 

  • Chang, C. C., Lin, D. Y., Fang, H. I., Chen, R. H. and Shih H. M., 2005, Daxx mediates the small ubiquitin-like modifier-dependent transcriptional repression of Smad4. J. Biol. Chem. 280, 10164–10173.

    Article  PubMed  CAS  Google Scholar 

  • Crum, T. L. and Okkema, P. G., 2007, SUMOylation-dependant function of a T-box transcriptional repressor in Caenorhabditis elegans. Biochem. Soc. Trans. 35, 1424–1426.

    Article  PubMed  CAS  Google Scholar 

  • Daniels, M., Shimizu, K., Zorn, A. M. and Ohnuma, S., 2004, Negative regulation of Smad2 by PIASy is required for proper Xenopus mesoderm formation. Development 131, 5613–5626.

    Article  PubMed  CAS  Google Scholar 

  • Dobreva, G., Chahrour, M., Dautzenberg, M., Chirivella, L., Kanzler, B., Fariñas, I., Karsenty, G. and Grosschedl. R., 2006, SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell 125, 971–986.

    Article  PubMed  CAS  Google Scholar 

  • FitzPatrick, D. R., Carr, I. M., McLaren, L., Leek, J. P., Wightman, P., Williamson, K., Gautier, P., McGill, N., Hayward, C., Firth, H., Markham, A. F., Fantes, J. A. and Bonthron, D. T., 2003, Identification of SATB2 as the cleft palate gene on 2q32-q33. Hum. Mol. Genet. 12, 2491–2501.

    Article  PubMed  CAS  Google Scholar 

  • Galy, B., Ferring, D., Benesova, M., Benes, V. and Hentze, M. W., 2004, Targeted mutagenesis of the murine IRP1 and IRP2 genes reveals context-dependant RNA processing differences in vivo. RNA 10, 1019–1025.

    Article  PubMed  CAS  Google Scholar 

  • Geiss-Friedlander, R. and Melchior, F., 2007, Concepts in sumoylation: a decade on. Nat. Rev. Mol. Cell Biol. 8, 947–956.

    Article  PubMed  CAS  Google Scholar 

  • Ghioni, P., D'Alessandra, Y., Mansueto, G., Jaffray, E., Hay, R. T., La Mantia, G. and Guerrini, L., 2005, The protein stability and transcriptional activity of p63alpha are regulated by SUMO-1 conjugation. Cell Cycle 4, 183–190.

    Article  PubMed  CAS  Google Scholar 

  • Gupta, V. and Bei, M., 2006, Modification of Msx1 by SUMO-1. Biochem. Biophys. Res. Commun. 345, 74–77.

    Article  PubMed  CAS  Google Scholar 

  • Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield, T. K., Weemaes, C. M. R. and Gartler, S. M., 1999, The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl. Acad. Sci. U.S.A. 96, 14412–14417.

    Article  PubMed  CAS  Google Scholar 

  • Hsu, Y. H., Sarker, K. P., Pot, I., Chan, A., Netherton, S. J. and Bonni, S., 2006, Sumoylated SnoN represses transcription in a promoter-specific manner. J. Biol. Chem. 281, 33008–33018.

    Article  PubMed  CAS  Google Scholar 

  • Huang, Y. P., Wu, G., Guo, Z., Osada, M.,, Fomenkov, T., Park, H. L., Trink, B., Sidransky, D., Fomenkov, A. and Ratovitski, E. A., 2004, Altered sumoylation of p63alpha contributes to the split-hand/foot malformation phenotype. Cell Cycle 3, 1587–1596.

    Article  PubMed  CAS  Google Scholar 

  • Izzi, L., Narimatsu, M. and Attisano, L., 2008, Sumoylation differentially regulates Goosecoid-mediated transcriptional repression. Exp. Cell Res. 314, 1585–1594.

    Article  PubMed  CAS  Google Scholar 

  • Jezewski, P. A., Vieira, A. R., Nishimura, C., Ludwig, B., Johnson, M., O'Brien, S. E., Daack-Hirsch, S., Schultz, R. E., Weber, A., Nepomucena, B., Romitti, P. A., Christensen, K., Orioli, I. M., Castilla, E. E., Machida, J., Natsume, N. and Murray, J. C., 2003, Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J. Med. Genet. 40, 399–407.

    Article  PubMed  CAS  Google Scholar 

  • Kaiser, F. J., Lüdecke, H. J. and Weger, S., 2007, SUMOylation modulates transcriptional repression by TRPS1. Biol. Chem. 388, 381–390.

    Article  PubMed  CAS  Google Scholar 

  • Kang, E. S., Park, C.W. and Chung, J. H., 2001, Dnmt3b, de novo DNA methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1. Biochem. Biophys. Res. Commun. 289, 862–868.

    Article  PubMed  CAS  Google Scholar 

  • Kang, J. S., Saunier, E. F., Akhurst, R. J. and Derynck, R., 2008, The I TGFb receptor is covalently modified and regulated by sumoylation. Nat. Cell Biol. 10, 654–664.

    Article  PubMed  CAS  Google Scholar 

  • Kondo, S., Schutte, B. C., Richardson, R. J., Bjork, B. C., Knight, A. S., Watanabe, Y., Howard, E., de Lima, R. L., Daack-Hirsch, S., Sander, A., McDonald-McGinn, D. M., Zackai, E. H., Lammer, E. J., Aylsworth, A. S., Ardinger, H. H., Lidral, A. C., Pober, B. R., Moreno, L., Arcos-Burgos, M., Valencia, C., Houdayer, C., Bahuau, M., Moretti-Ferreira, D., Richieri-Costa, A., Dixon, M. J. and Murray, J. C., 2002, Mutations in IRF6 cause Van der Woude, and popliteal pterygium syndromes. Nat. Genet. 32, 285–289.

    Article  PubMed  CAS  Google Scholar 

  • Lee, H., Quinn, J. C., Prasanth, K. V., Swiss, V. A., Economides, K. D., Camacho, M. M., Spector, D. L. and Abate-Shen, C., 2006, PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein. Genes Dev. 20, 784–794.

    Article  PubMed  CAS  Google Scholar 

  • Lee, P. S., Chang, C., Liu, D., and Derynck, R., 2003, Sumoylation of Smad4, the common Smad mediator of transforming growth factor-beta family signaling. J. Biol. Chem. 278, 27853–27863.

    Google Scholar 

  • Leoyklang, P., Suphapeetiporn, K., Siriwan, P., Desudchit, T., Chaowanapanja, P., Gahl, W. A. and Shotelersuk, V., 2007, Heterozygous nonsense mutation SATB2 associated with cleft palate, osteoporosis, and cognitive defects. Hum. Mutat. 28, 732–738.

    Article  PubMed  CAS  Google Scholar 

  • Liang, M., Melchior, F., Feng, X. H. and Lin, H., 2004, Regulation of Smad4 sumoylation and transforming growth factor-beta signalling by protein inhibitor of activated STAT1. J. Biol. Chem. 279, 22857–22865.

    Article  PubMed  CAS  Google Scholar 

  • Lidral, A. C. and Moreno, L. M., 2005, Progress toward discerning the genetics of cleft lip. Curr. Opin. Pediatr. 17, 731–739.

    Article  PubMed  Google Scholar 

  • Lin, X., Liang, M., Liang, Y. Y., Brunicardi, F. C., Melchior, F. and Feng, X. H., 2003, Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4. J. Biol. Chem. 278, 18714–18719.

    Article  PubMed  CAS  Google Scholar 

  • Long, J., Wang, G., He, D. and Liu, F., 2004, Repression of Smad4 transcriptional activity by SUMO modification. Biochem. J. 379, 23–29.

    Article  PubMed  CAS  Google Scholar 

  • Malik, T. H., Von Stechow, D., Bronson, R. T. and Shivdasani, R. A., 2002, Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhino-phalangeal syndromes. Mol. Cell. Biol. 22, 8592–8600.

    Article  PubMed  CAS  Google Scholar 

  • Marçano, A. C., Doudney, K., Braybrook, C., Squires, R., Patton, M. A., Lees, M. M., Richieri-Costa, A., Lidral, A. C., Murray, J. C., Moore, G. E., and Stanier, P., 2004, TBX22 mutations are a frequent cause of cleft palate. J. Med. Genet. 41, 68–74.

    Article  PubMed  Google Scholar 

  • Meulmeester, E., Kunze, M., Hsiao, H. H., Urlab, H. and Melchior, F., 2008, Mechanisms and consequences for paralog-specific sumoylation of ubiquitin-specific protease 25. Mol. Cell 30, 539–540.

    Article  Google Scholar 

  • Mills, A. A., Zheng, B., Wang, X. J., Vogel, H., Roop, D. R. and Bradley, A., 1999, p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713.

    Article  PubMed  CAS  Google Scholar 

  • Momeni, P., Glöckner, G., Schmidt, O., von Holtum, D., Albrecht, B., Gillessen-Kaesbach, G., Hennekam, R., Meinecke, P., Zabel, B., Rosenthal, A., Horsthemke, B. and Lüdecke, H. J., 2000, Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. Nat. Genet. 24, 71–74.

    Article  PubMed  CAS  Google Scholar 

  • Murray, J. C., 2002, Gene/environment causes of cleft lip and/or palate. Clin. Genet. 61, 248–256.

    Article  PubMed  CAS  Google Scholar 

  • Murray, J. C. and Schutte, B. C., 2004, Cleft palate: players, pathways, and pursits. J. Clin. Invest. 12, 1676–1678.

    Google Scholar 

  • Nacerddine, K., Lehembre, F., Bhumik, M., Artus, J., Cohen-Tannoudji, M., Babinet, C., Pandolfi, P. P. and Dejean, A., 2005, The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev. Cell 9, 769–799.

    Article  PubMed  CAS  Google Scholar 

  • Park, J., Kim, T. Y., Jung, Y., Song, S. H., Oh, D. Y., Im, S. A. and Bang, Y. J., 2008, DNA methylytransferase 3B mutant in ICF syndrome interacts non-covalently with SUMO-1. J. Mol. Med. 86, 1269–1277.

    Article  PubMed  CAS  Google Scholar 

  • Pauws, E. and Stanier, P., 2007, FGF signalling and SUMO modification: new players in the aetiology of cleft lip and/or palate. Trends Genet. 12, 631–640.

    Article  Google Scholar 

  • Rinne, T., Brunner, H. G. and van Bokhoven, H., 2007, p63-associated disorders. Cell Cycle 6, 262–268.

    Article  PubMed  CAS  Google Scholar 

  • Rivera-Perez, J. A., Mallo, M., Gendon-Maguire, M., Gridley, T. and Behringer, R. R., 1999, Goosecoid acts cell autonomously in mesenchyme-derived tissues during craniofacial development. Development 121, 3005–3012.

    Google Scholar 

  • Roy Chowdhuri, S., Crum, T., Woollard, A., Aslam, S. and Okkema, P. G., 2006, The T-box transcription factor TBX-2 and the SUMO conjugating enzyme UBC-9 are required for ABa-derived pharyngeal muscle in C. elegans. Dev. Biol. 295, 664–677.

    Article  PubMed  Google Scholar 

  • Rui, H. L., Fan, E., Zhou, H. M., Xu, Z., Zhang, Y. and Lin, S. C., 2002, SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling. J. Biol. Chem. 277, 42981–42986.

    Article  PubMed  CAS  Google Scholar 

  • Sachdev, S., Bruhn, L., Sieber, H., Pichler, A., Melchior, F. and Grosschedl, R., 2001, PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15, 3088–3103.

    Article  PubMed  CAS  Google Scholar 

  • Satokata, I. and Maas, R., 1994, Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat. Genet. 6, 348–356.

    Article  PubMed  CAS  Google Scholar 

  • Seeler, J. S. and Dejean, A., 2003, Nuclear and unclear functions of SUMO. Nat. Rev. Mol. Cell Biol. 4, 690–699.

    Article  PubMed  CAS  Google Scholar 

  • Shi, M., Christensen, K., Weinberg, C. R., Romitti, P., Bathum, L., Lozada, A., Morris, R. W., Lovett, M. and Murray, J. C., 2007, Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants. Am. J. Hum. Genet. 80, 76–90.

    Article  PubMed  CAS  Google Scholar 

  • Shimada, K., Suzuki, N., Ono, Y., Tanaka, K., Maeno, M. and Ito, K., 2008, Ubc9 promotes the stability of SMad4 and the nuclear accumulation of Smad1 in osteoblast-like saos-2 cells. Bone 42, 886–893.

    Article  PubMed  CAS  Google Scholar 

  • Sramko, M., Markus, J., Kabát, J., Wolff, L. and Bies, J., 2006, Stress-induced inactivation of the c-Myb transcription factor through conjugation of SUMO-2/3 proteins. J. Biol. Chem. 281, 40065–40075.

    Article  PubMed  CAS  Google Scholar 

  • Stanier, P. and Moore, G. E., 2004, Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts. Hum. Mol. Gen. 13, R73–R81.

    Article  PubMed  CAS  Google Scholar 

  • Suphapeetiporn, K., Tongkobpetch, S., Siriwan, P. and Shotelersuk, V., 2007, TBX22 mutations are a frequent cause of non-syndromic cleft palate in the Thai population. Clin. Genet. 72, 78–83.

    Article  Google Scholar 

  • Taylor, K. M. and Labonne, C., 2005, SoxE factors function equivalently during neural crest and inner ear development and their activity is regulated by SUMOylation. Dev. Cell 9, 593–603.

    Article  PubMed  CAS  Google Scholar 

  • Tempe, D., Piechaczyk, M. and Bossis, G., 2008, SUMO under stress. Bioch. Soc. Trans. 36, 874–878.

    Article  CAS  Google Scholar 

  • Thomason, H. A., Dixon, M. J. and Dixon, J., 2008, Facial clefting in Tp63 deficient mice results from altered Bmp4, Fgf8 and Shh signalling. Dev. Biol. 321, 273–282.

    Article  PubMed  CAS  Google Scholar 

  • Tsuruzoe, S., Ishihara, K., Uchimura, Y., Watanabe, S., Sekita, Y., Aoto, T., Saitoh, H., Yuasa, Y., Niwa, H., Kawasuji, M., Baba, H. and Nakao, M., 2006, Inhibition of DNA binding of Sox2 by the SUMO conjugation. Biochem. Biophys. Res. Commun. 351, 920–926.

    Article  PubMed  CAS  Google Scholar 

  • van den Boogaard, M.-J. H., Dorland, M., Beemer, F. A. and van Amstel, H. K. P., 2000, MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat. Genet. 24, 342–343.

    Article  PubMed  Google Scholar 

  • Vieira, A. R., Avila, J. R., Daack-Hirsch, S., Dragan, E., Félix, T. M., Rahimov, F., Harrington, J., Schultz, R. R., Watanabe, Y., Johnson, M., Fang, J., O'Brien, S. E., Orioli, I. M., Castilla, E. E., Fitzpatrick, D. R., Jiang, R., Marazita, M. L. and Murray, J. C., 2005, Medical sequencing of candidate genes for nonsyndromic cleft lip and palate. PLoS. Genet. 1, e64

    Article  PubMed  Google Scholar 

  • Wrighton, K. H., Liang, M., Bryan, B., Luo, K., Liu, M., Feng, X. H. and Lin, X., 2007, Transforming growth factor-beta-independent regulation of myogenesis by SnoN sumoylation. J. Biol. Chem. 282, 6517–6524.

    Article  PubMed  CAS  Google Scholar 

  • Wyszynski, D. F., Beaty, T. H. and Maestri, N. E., 1996, Genetics of nonsyndromic oral clefts revisited. Cleft Palate J. 33, 406–417.

    Article  CAS  Google Scholar 

  • Xu, G. L., Bestor, T. H., Bourc’his, D., Hsieh, C. L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J. and Viegas-Pequignot, E., 1999a, Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191.

    Article  PubMed  CAS  Google Scholar 

  • Xu, P. X., Adams, J., Peters, H., Brown, M. C., Heaney, S and Maas, R., 1999b, Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordial. Nat. Genet. 23, 113–117.

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto, H., Ihara, M., Matsuura, Y. and Kikuchi, A., 2003, Sumoylation is involved in β-catenin-dependent activation of Tcf-4. EMBO J. 22, 2047–2059.

    Article  PubMed  CAS  Google Scholar 

  • Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R. T., Tabin, C., Sharpe, A., Caput, D., Crum, C. and McKeon, F., 1999, p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718.

    Article  PubMed  CAS  Google Scholar 

  • Yukita, A., Michiue, T., Asashima, M., Sakurai, K., Yamamoto, H., Ihara, M., Kikuchi, A. and Asashima, M., 2004, XSENP1, a novel sumo-specific protease in Xenopus, inhibits normal head formation by down-regulation of Wnt/β-catenin signalling. Genes Cells 9, 723–736.

    Article  PubMed  CAS  Google Scholar 

  • Yukita, A., Michiue, T., Danno, H. and Asashima, M., 2007, XSUMO-1 is required for normal mesoderm induction and axis elongation during early Xenopus development. Dev. Dyn. 236, 2757–2766.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, F.-P., Mikkonen, L., Toppari, J., Palvimo, J. J., Thesleff, I. and Janne, O. A., 2008, Sumo-1 function is dispensable in normal mouse development. Mol. Cell. Biol. 28, 5381–5390.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neural Development Unit, Institute of Child Health, University College London, WC1N 1EH, London, UK

    Erwin Pauws & Philip Stanier

Authors
  1. Erwin Pauws
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip Stanier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philip Stanier .

Editor information

Editors and Affiliations

  1. College Station, 77843-1114, U.S.A.

    Van G. Wilson

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Pauws, E., Stanier, P. (2009). Sumoylation in Craniofacial Disorders. In: Wilson, V. (eds) SUMO Regulation of Cellular Processes. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2649-1_17

Download citation

Publish with us

Policies and ethics

Search

Navigation