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EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex
Lee, J.,Lee, Jason S.,Kim, H.,Kim, K.,Park, H.,Kim, J.Y.,Lee, S.,Kim, I.,Kim, J.,Lee, M.,Chung, C.,Seo, S.B.,Yoon, J.B.,Ko, E.,Noh, D.Y.,Kim, K.,Kim, K.,Baek, S. Cell Press 2012 Molecular cell Vol.48 No.4
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.
Negative Regulation of Hypoxic Responses via Induced Reptin Methylation
Lee, Jason S.,Kim, Yunho,Kim, Ik Soo,Kim, Bogyou,Choi, Hee June,Lee, Ji Min,Shin, Hi-Jai R.,Kim, Jung Hwa,Kim, Ji-Young,Seo, Sang-Beom,Lee, Ho,Binda, Olivier,Gozani, Or,Semenza, Gregg L.,Kim, Minhyung Elsevier 2010 Molecular cell Vol.39 No.1
<P><B>Summary</B></P><P>Lysine methylation within histones is crucial for transcriptional regulation and thus links chromatin states to biological outcomes. Although recent studies have extended lysine methylation to nonhistone proteins, underlying molecular mechanisms such as the upstream signaling cascade that induces lysine methylation and downstream target genes modulated by this modification have not been elucidated. Here, we show that Reptin, a chromatin-remodeling factor, is methylated at lysine 67 in hypoxic conditions by the methyltransferase G9a. Methylated Reptin binds to the promoters of a subset of hypoxia-responsive genes and negatively regulates transcription of these genes to modulate cellular responses to hypoxia.</P> <P><B>Highlights</B></P><P>► Reptin is a target of G9a methyltransferase ► Reptin K67 methylation is induced by hypoxia ► Genome-wide identification of hypoxia target genes negatively regulated by Reptin ► Hypoxia-driven Reptin methylation negatively regulates tumorigenic behavior in vivo</P>
Spatiotemporal genomic architecture informs precision oncology in glioblastoma
Lee, Jin-Ku,Wang, Jiguang,Sa, Jason K,Ladewig, Erik,Lee, Hae-Ock,Lee, In-Hee,Kang, Hyun Ju,Rosenbloom, Daniel S,Camara, Pablo G,Liu, Zhaoqi,van Nieuwenhuizen, Patrick,Jung, Sang Won,Choi, Seung Won,Ki Nature Pub. Co 2017 Nature genetics Vol.49 No.4
<P>Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies1-5. However, this proposition is complicated by spatial and temporal heterogeneity6-14. Here we study genomic and expression profiles across 127 multisector or longitudinal specimens from 52 individuals with glioblastoma (GBM). Using bulk and single-cell data, we find that samples from the same tumor mass share genomic and expression signatures, whereas geographically separated, multifocal tumors and/or long-term recurrent tumors are seeded from different clones. Chemical screening of patient-derived glioma cells (PDCs) shows that therapeutic response is associated with genetic similarity, and multifocal tumors that are enriched with PIK3CA mutations have a heterogeneous drug-response pattern. We show that targeting truncal events is more efficacious than targeting private events in reducing the tumor burden. In summary, this work demonstrates that evolutionary inference from integrated genomic analysis in multisector biopsies can inform targeted therapeutic interventions for patients with GBM.</P>
DNA Damage-Induced RORα Is Crucial for p53 Stabilization and Increased Apoptosis
Kim, H.,Lee, J.,Lee, G.,Bhin, J.,Oh, S.,Kim, K.,Pyo, K.,Lee, Jason S.,Yim, H.,Kim, K.,Hwang, D.,Chung, J.,Baek, S. Cell Press 2011 Molecular cell Vol.44 No.5
A critical component of the DNA damage response is the p53 tumor suppressor, and aberrant p53 function leads to uncontrolled cell proliferation and malignancy. Several molecules have been shown to regulate p53 stability; however, genome-wide systemic approaches for determining the affected, specific downstream target genes have not been extensively studied. Here, we first identified an orphan nuclear receptor, RORα, as a direct target gene of p53, which contains functional p53 response elements. The functional consequences of DNA damage-induced RORα are to stabilize p53 and activate p53 transcription in a HAUSP/Usp7-dependent manner. Interestingly, microarray analysis revealed that RORα-mediated p53 stabilization leads to the activation of a subset of p53 target genes that are specifically involved in apoptosis. We further confirmed that RORα enhances p53-dependent, in vivo apoptotic function in the Drosophila model system. Together, we determined that RORα is a p53 regulator that exerts its role in increased apoptosis via p53.
CD55 polymorphisms and risk of aspirin-exacerbated respiratory disease
LEE, JIN SOL,BAE, JOON SEOL,KIM, JEONG-HYUN,KIM, JASON YONGHA,PARK, TAE JOON,PASAJE, CHARISSE FLERIDA,PARK, BYUNG-LAE,CHEONG, HYUN SUB,UH, SOO-TAEK,JANG, AN-SOO,CHOI, INSEON S.,PARK, CHOON-SIK,SHIN, H Spandidos Publications 2012 MOLECULAR MEDICINE REPORTS Vol.6 No.5
<P>Aspirin-exacerbated respiratory disease (AERD) is a respiratory disease characterized by acute bronchial responses upon the administration of non-steroidal anti?inflammatory drugs (NSAIDs) and the immune response by mast cells is regarded as one of the noteworthy causes of AERD pathogenesis. The complement cascade is regarded as a key mechanism for clearing pathogens from the host. CD55 is one of the proteins involved in self-recognition, a central component of the complement system and autoimmunity. To investigate the associations between CD55 single nucleotide polymorphisms (SNPs) and the risk of AERD, we carried out logistic analyses with three genetic models and further regression analysis was performed with the fall rate of forced expiratory volume in 1?sec (FEV1) by aspirin provocation. However, our results demonstrate that no CD55 polymorphisms are associated with the risk of AERD and the fall rate of FEV1 (P>0.05). Therefore, our results suggest that CD55 polymorphisms are not genetic markers of aspirin?induced bronchospasm, including FEV1, in the population studied. Although the genetic role of CD55 has been found to be integral to human immunity, our results indicate that genetic variations of CD55 do not influence the risk of AERD and the fall rate of FEV1 in the population studied.</P>
Cardiorenal Protection in Diabetic Kidney Disease
Jason F. Lee,Ecaterina Berzan,Vikas S. Sridhar,Ayodele Odutayo,David Z.I. Cherney 대한내분비학회 2021 Endocrinology and metabolism Vol.36 No.2
Over the last 5 years there have been many new developments in the management of diabetic kidney disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT2) inhibitors were initially used for glycemic control, but more recent studies have now shown that their benefits extend to cardiovascular and kidney outcomes. The recent additionof data on the novel mineralocorticoid receptor antagonist (MRA) gives us another approach to further decrease the residual risk ofdiabetic kidney disease progression. In this review we describe the mechanism of action, key studies, and possible adverse effects related to these three classes of medications. The management of type 2 diabetes now includes an increasing number of medicationsfor the management of comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronickidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors, GLP-1 RA and MRAs in patients with type 2 diabetes for heart and kidney protection.
Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy
Lee, Jin-Ku,Liu, Zhaoqi,Sa, Jason K.,Shin, Sang,Wang, Jiguang,Bordyuh, Mykola,Cho, Hee Jin,Elliott, Oliver,Chu, Timothy,Choi, Seung Won,Rosenbloom, Daniel I. S.,Lee, In-Hee,Shin, Yong Jae,Kang, Hyun J Nature Pub. Co 2018 Nature genetics Vol.50 No.10