EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex - PubMed (original) (raw)

. 2012 Nov 30;48(4):572-86.

doi: 10.1016/j.molcel.2012.09.004. Epub 2012 Oct 11.

Jason S Lee, Hyunkyung Kim, Kyeongkyu Kim, Hyejin Park, Ji-Young Kim, Seung Hoon Lee, Ik Soo Kim, Joomyung Kim, Minkyoung Lee, Chin Ha Chung, Sang-Beom Seo, Jong-Bok Yoon, Eunyoung Ko, Dong-Young Noh, Keun Il Kim, Kyeong Kyu Kim, Sung Hee Baek

Affiliations

• PMID: 23063525
• DOI: 10.1016/j.molcel.2012.09.004

Free article

EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex

Ji Min Lee et al. Mol Cell. 2012.

Free article

Abstract

Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing "methyl degron"; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.

Copyright © 2012 Elsevier Inc. All rights reserved.

PubMed Disclaimer

Comment in

• Titivated for destruction: the methyl degron.
  Yang Y, Bedford MT. Yang Y, et al. Mol Cell. 2012 Nov 30;48(4):487-8. doi: 10.1016/j.molcel.2012.11.007. Mol Cell. 2012. PMID: 23200121 Free PMC article.

Similar articles

• Arabidopsis DDB1-CUL4 ASSOCIATED FACTOR1 forms a nuclear E3 ubiquitin ligase with DDB1 and CUL4 that is involved in multiple plant developmental processes.
  Zhang Y, Feng S, Chen F, Chen H, Wang J, McCall C, Xiong Y, Deng XW. Zhang Y, et al. Plant Cell. 2008 Jun;20(6):1437-55. doi: 10.1105/tpc.108.058891. Epub 2008 Jun 13. Plant Cell. 2008. PMID: 18552200 Free PMC article.
• CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation.
  Higa LA, Wu M, Ye T, Kobayashi R, Sun H, Zhang H. Higa LA, et al. Nat Cell Biol. 2006 Nov;8(11):1277-83. doi: 10.1038/ncb1490. Epub 2006 Oct 15. Nat Cell Biol. 2006. PMID: 17041588
• Interactions with DCAF1 and DDB1 in the CRL4 E3 ubiquitin ligase are required for Vpr-mediated G2 arrest.
  Hakata Y, Miyazawa M, Landau NR. Hakata Y, et al. Virol J. 2014 Jun 9;11:108. doi: 10.1186/1743-422X-11-108. Virol J. 2014. PMID: 24912982 Free PMC article.
• DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase.
  Lee J, Zhou P. Lee J, et al. Mol Cell. 2007 Jun 22;26(6):775-80. doi: 10.1016/j.molcel.2007.06.001. Mol Cell. 2007. PMID: 17588513 Review.
• The functions of the HIV1 protein Vpr and its action through the DCAF1.DDB1.Cullin4 ubiquitin ligase.
  Casey L, Wen X, de Noronha CM. Casey L, et al. Cytokine. 2010 Jul;51(1):1-9. doi: 10.1016/j.cyto.2010.02.018. Epub 2010 Mar 27. Cytokine. 2010. PMID: 20347598 Free PMC article. Review.

Cited by

• Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.
  Seneviratne JA, Ravindrarajah D, Carter DR, Zhai V, Lalwani A, Krishan S, Balachandran A, Ng E, Pandher R, Wong M, Nero TL, Wang S, Norris MD, Haber M, Liu T, Parker MW, Cheung BB, Marshall GM. Seneviratne JA, et al. Cancer Med. 2024 Nov;13(21):e70082. doi: 10.1002/cam4.70082. Cancer Med. 2024. PMID: 39501501 Free PMC article.
• Regulation of RORα Stability through PRMT5-Dependent Symmetric Dimethylation.
  Xiong G, Obringer B, Jones A, Horton E, Xu R. Xiong G, et al. Cancers (Basel). 2024 May 17;16(10):1914. doi: 10.3390/cancers16101914. Cancers (Basel). 2024. PMID: 38791992 Free PMC article.
• SUV39H1-driven NFATc1 methylation is essential for the c-Cbl-mediated degradation of NFATc1 in an osteoclast lineage.
  Jeong DW, Kim HJ, Park JW, Lee S, Jung H, Yi EC, Kim N, Chun YS. Jeong DW, et al. Genes Dis. 2023 Jul 14;11(4):101034. doi: 10.1016/j.gendis.2023.06.008. eCollection 2024 Jul. Genes Dis. 2023. PMID: 38510482 Free PMC article. No abstract available.
• CRL4b Inhibition Ameliorates Experimental Autoimmune Encephalomyelitis Progression.
  Dar AA, Ortega Y, Aktas S, Wu K, Guha I, Porter N, Rosen S, DeVita RJ, Pan ZQ, Oliver PM. Dar AA, et al. J Immunol. 2024 Mar 15;212(6):982-991. doi: 10.4049/jimmunol.2300754. J Immunol. 2024. PMID: 38265261
• A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition.
  Gao CW, Lin W, Riddle RC, Kushwaha P, Boukas L, Björnsson HT, Hansen KD, Fahrner JA. Gao CW, et al. JCI Insight. 2024 Jan 9;9(1):e173392. doi: 10.1172/jci.insight.173392. JCI Insight. 2024. PMID: 38015625 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • H1 Connect
  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • GlyGen glycoinformatics resource
  • Mouse Genome Informatics (MGI)

• Research Materials

  • NCI CPTC Antibody Characterization Program