Methylation-state-specific recognition of histones by the MBT repeat protein L3MBTL2

Guo, Yahong; Nady, Nataliya; Chen, Qi; Allali-Hassani, Abdellah; Zhu, Haizhong; Pan, Patricia; Adams-Cioaba, Melanie A.; Amaya, M.F.; Dong, Aiping; Vedadi, Masoud; Schapira, Matthieu; Read, Randy J.; Arrowsmith, C.H.; Min, Jinrong

doi:10.1093/nar/gkp086

Cited by 87 publications

(109 citation statements)

References 35 publications

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“…52,53 Significantly, K26me3 peptide does not bind to L3MBTL1. [53][54][55] Similar observations were made in the context of L3MBTL1 binding to H4K20 methylated peptides, where the tri-methylated peptide does not bind. [53][54][55] Histone H1 K26 tri-methylation has also been observed to potently inhibit the PRC2 methyltransferase activity on the nucleosome by binding the EED subunit of the complex.…”

Section: Prc2 In Stem Cell Differentiation and Somatic Cell Reprogramsupporting

confidence: 68%

Composition, recruitment and regulation of the PRC2 complex

Nayak

Xu²,

Min³

2011

Nucleus

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T he PRC2 histone methyltransferase complex is an important regulator of gene expression programs in metazoans. Gene expression regulation by the PRC2 complex is critical for development and cell differentiation. Several recent studies have begun to shed light on the molecular basis for the physiological function of the PRC2 complex. Here, we discuss some of these results and how they provide new insights into the composition, recruitment and regulation of the PRC2 complex.

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Section: Prc2 In Stem Cell Differentiation and Somatic Cell Reprogramsupporting

confidence: 68%

Composition, recruitment and regulation of the PRC2 complex

Nayak

Xu²,

Min³

2011

Nucleus

Self Cite

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“…S1). This binding mode is similar to the mechanism by which L3MBTL1 3xMBT , Tudor domain and engineered plant homeodomain (PHD) fingers, recognize mono-and dimethylated lysine residues of histones (16,20,28), suggesting conservation for readout of the lowmethylation state.…”

Section: The 3xmbt Repeat Of L3mbtl1 Recognizes P53k382me1 Inmentioning

confidence: 61%

The MBT Repeats of L3MBTL1 Link SET8-mediated p53 Methylation at Lysine 382 to Target Gene Repression

West

Roy

Lachmi-Weiner

et al. 2010

Journal of Biological Chemistry

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The p53 tumor suppressor protein is regulated by multiple post-translational modifications, including lysine methylation. We previously found that monomethylation of p53 at lysine 382 (p53K382me1) by the protein lysine methyltransferase (PKMT) SET8/PR-Set7 represses p53 transactivation of target genes. However, the molecular mechanism linking p53K382 monomethylation to repression is not known. Here we show in biochemical and crystallographic studies the preferential recognition of p53K382me1 by the triple malignant brain tumor (MBT) repeats of the chromatin compaction factor L3MBTL1. We demonstrate that SET8-mediated methylation of p53 at Lys-382 promotes the interaction between L3MBTL1 and p53 in cells, and the chromatin occupancy of L3MBTL1 at p53 target promoters. In the absence of DNA damage, L3MBTL1 interacts with p53K382me1 and p53-target genes are repressed, whereas depletion of L3MBTL1 results in a p53-dependent increase in p21 and PUMA transcript levels. Activation of p53 by DNA damage is coupled to a decrease in p53K382me1 levels, abrogation of the L3MBTL1-p53 interaction, and disassociation of L3MBTL1 from p53-target promoters. Together, we identify L3MBTL1 as the second known methyl-p53 effector protein, and provide a molecular explanation for the mechanism by which p53K382me1 is transduced to regulate p53 activity.The reversible and dynamic methylation of proteins on the nitrogen side-chain of lysine residues can greatly increase the signaling potential of the modified factor (1, 2). Lysine residues can accept up to three methyl groups, forming mono-, di-, and trimethylated derivatives, with a unique activity frequently being coupled to the specific methylation state. The chemical addition of methyl moieties to histones is not believed to intrinsically affect chromatin structure. Rather, the principal mechanism by which histone lysine methylation is thought to manifest functionally occurs through regulation of modular protein-protein interactions (3-5). In this regard, the protein(s) that recognize a methylated lysine within a specific sequence context can define the functional outcome associated with that specific lysine methylation event. Thus, mechanistic insight into how lysine methylation influences a biological program requires knowledge of the proteins and domains that recognize and transduce this modification.In addition to histones, several other proteins such as the tumor suppressor p53 undergo lysine methylation, arguing that this modification may be a common mechanism for modulating protein-protein interactions and key cellular signaling pathways (6 -8). p53 plays a pivotal role in the regulation of cellular responses to various forms of genotoxic stresses, and its activity is coordinated by a complex network of post-translational modifications (9, 10). We previously demonstrated that the protein lysine methyltransferase (PKMT) 5 PR-Set7/SET8 monomethylates p53 exclusively at lysine 382 (p53K382me1), and that the placement of this modification negatively regulates p53 activity (11). Spec...

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“…Hence, increased EZH2 expression in E7-expressing cells may be predicted to cause enhanced H1K26 methylation. Intriguingly, HPV16 E7 is associated with the L3MBTL2 protein (9), which is closely related to L3MBTL1 (33), and it will be interesting to determine whether the predicted increase in EZH2-containing PRC4 complexes and association with L3MBTL2 may alter H1K26 methylation (Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming

McLaughlin-Drubin

Crum²,

Münger³

2011

Proc. Natl. Acad. Sci. U.S.A.

280

297

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Despite the availability of vaccines, human papillomavirus (HPV) infections remain a cause of significant cancer morbidity and mortality. We have previously shown that HPV16 E7 associates with and diminishes E2F6-containing polycomb repressive complexes. Here, we show that repressive trimethyl marks on lysine 27 of histone 3, which are necessary for binding of polycomb repressive complexes, are decreased in HPV16 E7-expressing cells and HPV16-positive cervical lesions. This is caused by transcriptional induction of the KDM6A and KDM6B histone 3 lysine 27-specific demethylases. HPV16 E7-mediated KDM6B induction accounts for expression of the cervical cancer biomarker, p16 INK4A. Moreover, KDM6A-and KDM6B-responsive Homeobox genes are expressed at significantly higher levels, suggesting that HPV16 E7 results in reprogramming of host epithelial cells. These effects are independent of the ability of E7 to inhibit the retinoblastoma tumor suppressor protein. Most importantly, these effects are reversed when E7 expression is silenced, indicating that this pathway may have prognostic and/or therapeutic significance. The HPV E6 and E7 proteins lack intrinsic enzymatic activities and do not act as DNA binding transcription factors; rather, they reprogram their host cells by associating with cellular signaling molecules. High-risk HPV E6 proteins target the p53 tumor suppressor for degradation, thereby thwarting p53-mediated transcriptional cytostatic and cytotoxic responses to cellular stress signals. High-risk HPV E7 oncoproteins associate with and degrade the retinoblastoma tumor suppressor (pRB), which acts as a cell cycle-specific repressive subunit of several E2F transcriptional complexes, and thereby, subvert cell cycle-dependent E2F transcriptional activities (reviewed in ref.2). The HPV E6 and E7 oncoproteins also associate with enzymes that modulate histone acetylation and thus, broadly regulate the transcriptional competence of host cell chromatin (3-8).We have previously reported that the HPV16 E7 oncoprotein associates with E2F6-containing polycomb transcriptional repressor complexes (PRCs) and that the detection of these complexes is reduced in HPV16 E7-expressing cells (9). PRCs require the histone H3 lysine 27 trimethyl (H3K27me3) mark to associate with and transcriptionally silence chromatin (reviewed in ref. 10). PRCs have been most extensively studied in Drosophila melanogaster (reviewed in ref. 11), where they establish and sustain lineage-specific epigenetic silencing of Homeobox (HOX) genes during development (12, 13). HOX proteins are master regulators of transcriptional programs that create and maintain cellular identities. Other PRC-regulated genes include the INK4A-ARF tumor suppressor locus, which encodes p16INK4A , an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, and p14 ARF , an inhibitor of mdm2-mediated p53 degradation (14). Silencing through H3K27me3 involves PRC2 and PRC1. The catalytic subunit of PRC2, EZH2, is a methyl transferase that catalyzes di-and trimethylation of H3K27, whi...

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Methylation-state-specific recognition of histones by the MBT repeat protein L3MBTL2

Cited by 87 publications

References 35 publications

Composition, recruitment and regulation of the PRC2 complex

Composition, recruitment and regulation of the PRC2 complex

The MBT Repeats of L3MBTL1 Link SET8-mediated p53 Methylation at Lysine 382 to Target Gene Repression

Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming

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