EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex

Ji Min Lee, 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

Research output: Contribution to journalArticle

108 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)572-586
Number of pages15
JournalMolecular Cell
Volume48
Issue number4
DOIs
Publication statusPublished - 2012 Nov 30

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Ubiquitin-Protein Ligases
Ubiquitination
DNA-Binding Proteins
Methylation
Protein Stability
Orphan Nuclear Receptors
Methyltransferases
Substrate Specificity
Histones
Proteolysis
Phosphorylation
Enhancer of Zeste Homolog 2 Protein
Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Lee, J. M., Lee, J. S., Kim, H., Kim, K., Park, H., Kim, J. Y., ... Baek, S. H. (2012). EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex. Molecular Cell, 48(4), 572-586. https://doi.org/10.1016/j.molcel.2012.09.004
Lee, Ji Min ; Lee, Jason S. ; Kim, Hyunkyung ; Kim, Kyeongkyu ; Park, Hyejin ; Kim, Ji Young ; Lee, Seung Hoon ; Kim, Ik Soo ; Kim, Joomyung ; Lee, Minkyoung ; Chung, Chin Ha ; Seo, Sang Beom ; Yoon, Jong-Bok ; Ko, Eunyoung ; Noh, Dong Young ; Kim, Keun Il ; Kim, Kyeong Kyu ; Baek, Sung Hee. / EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex. In: Molecular Cell. 2012 ; Vol. 48, No. 4. pp. 572-586.
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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.",
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Lee, JM, Lee, JS, Kim, H, Kim, K, Park, H, Kim, JY, Lee, SH, Kim, IS, Kim, J, Lee, M, Chung, CH, Seo, SB, Yoon, J-B, Ko, E, Noh, DY, Kim, KI, Kim, KK & Baek, SH 2012, 'EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex', Molecular Cell, vol. 48, no. 4, pp. 572-586. https://doi.org/10.1016/j.molcel.2012.09.004

EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex. / Lee, Ji Min; Lee, Jason S.; Kim, Hyunkyung; Kim, Kyeongkyu; Park, Hyejin; Kim, Ji Young; Lee, Seung Hoon; Kim, Ik Soo; Kim, Joomyung; Lee, Minkyoung; Chung, Chin Ha; Seo, Sang Beom; Yoon, Jong-Bok; Ko, Eunyoung; Noh, Dong Young; Kim, Keun Il; Kim, Kyeong Kyu; Baek, Sung Hee.

In: Molecular Cell, Vol. 48, No. 4, 30.11.2012, p. 572-586.

Research output: Contribution to journalArticle

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T1 - EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex

AU - Lee, Ji Min

AU - Lee, Jason S.

AU - Kim, Hyunkyung

AU - Kim, Kyeongkyu

AU - Park, Hyejin

AU - Kim, Ji Young

AU - Lee, Seung Hoon

AU - Kim, Ik Soo

AU - Kim, Joomyung

AU - Lee, Minkyoung

AU - Chung, Chin Ha

AU - Seo, Sang Beom

AU - Yoon, Jong-Bok

AU - Ko, Eunyoung

AU - Noh, Dong Young

AU - Kim, Keun Il

AU - Kim, Kyeong Kyu

AU - Baek, Sung Hee

PY - 2012/11/30

Y1 - 2012/11/30

N2 - 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.

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