Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance

Migliori, Valentina; Müller, Julius; Phalke, Sameer; Low, Diana; Bezzi, Marco; Mok, Wei Chuen; Sahu, Sanjeeb Kumar; Gunaratne, Jayantha; Capasso, Paola; Bassi, C.; Cecatiello, Valentina; Marco, Ario de; Blackstock, Walter; Kuznetsov, Vladimir A.; Amati, Bruno; Mapelli, Marina; Guccione, Ernesto

doi:10.1038/nsmb.2209

Cited by 288 publications

(300 citation statements)

References 54 publications

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“…The difference in the results could be related to the use of synthetic chromatin in vitro transcription assay 34 versus the in vitro reporter gene assay and in vivo infection studies (this study). It is also possible that the difference was owing to symmetric versus asymmetric arginine dimethylation that is known to have opposite effects on transcription 36,37 . Structure-based characterization of methyltransferase activity of Rv1988 would be able to shed light on this difference.…”

Section: Discussionmentioning

confidence: 99%

Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3

et al. 2015

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“…WDR5 binds both unmethylated and lysine mono-, di-, and trimethylated histone H3K4 peptides, and has recently been shown to differentiate between symmetric and asymmetric arginine di-methylation by specifically recognizing H3R2me2s (39). Peptides bind WDR5 on the top surface of the β-propeller domain, inserting the side-chain of Arg2 into the central channel where the guanidine group packs between the side-chains of Phe133 and Phe263.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of the human PRMT5:MEP50 complex

Antonysamy

Bonday

Campbell

et al. 2012

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

275

385

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Protein arginine methyltransferases (PRMTs) play important roles in several cellular processes, including signaling, gene regulation, and transport of proteins and nucleic acids, to impact growth, differentiation, proliferation, and development. PRMT5 symmetrically di-methylates the two-terminal ω-guanidino nitrogens of arginine residues on substrate proteins. PRMT5 acts as part of a multimeric complex in concert with a variety of partner proteins that regulate its function and specificity. A core component of these complexes is the WD40 protein MEP50/WDR77/p44, which mediates interactions with binding partners and substrates. We have determined the crystal structure of human PRMT5 in complex with MEP50 (methylosome protein 50), bound to an S-adenosylmethionine analog and a peptide substrate derived from histone H4. The structure of the surprising hetero-octameric complex reveals the close interaction between the seven-bladed β-propeller MEP50 and the N-terminal domain of PRMT5, and delineates the structural elements of substrate recognition.epigenetics | protein-protein complex | A9145C P osttranslational methylation of lysine and arginine residues by protein lysine methyltransferases and protein arginine methyltransferases (PRMTs) alters the activity and interactions of substrate proteins, with crucial consequences to diverse cellular functions (1-3). Histone methylation is an epigenetic mark that plays a vital role in normal cell function, and whose dysregulation is associated with several diseases (4).The PRMT family of methyltransferases belongs to the largest class (class I) of S-adenosylmethionine (AdoMet)-dependent methyltransferase enzymes, responsible for the transfer of a methyl group from AdoMet to the arginine side-chains of histones and other proteins. PRMTs are further subdivided into type I, type II, type III, and type IV enzymes based on their patterns of arginine methylation. Eleven human PRMTs have been identified to date (5), and they all methylate the terminal guanidino nitrogen atoms of arginine residues. Type I PRMT enzymes (PRMT1, -2, -3, -4, -6, and -8) generate ω-NG-monomethyl and ω-NG,NG-asymmetric di-methyl arginines, whereas PRMT5 is a type II PRMT that catalyzes the formation of ω-NG-monomethyl and ω-NG,N′G-symmetric di-methyl arginine residues. PRMT7 was initially thought to have type II activity, but recent evidence suggests that it may be a type III enzyme that is only able to monomethylate substrates to form ω-NG-monomethyl arginine (6). A type IV enzyme that catalyses the formation of δ-N-methyl arginine has been identified in yeast (7). All PRMTs share the highly conserved methyltransferase catalytic domain, and several PRMTs contain additional domains that modulate their activity and specificity. PRMT2, PRMT3, and PRMT9 contain SH3, zinc finger, and TRP2 domains, respectively, and PRMT5 contains a largely uncharacterized N-terminal region.In contrast to type I PRMTs, PRMT5 functions as part of various high molecular weight protein complexes that invariably contain the WD-repe...

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“…Trimethylation of histone H3K9 is well known to be associated with transcriptional suppression (31), but the role of H3-R2 methylation has just started to be unveiled (32)(33)(34)(35). Recently, H3-R2 binding of UHRF1 was shown to be dispensable for localization of UHRF1 at pericentromeric heterochromatin (19,20).…”

Section: Discussionmentioning

confidence: 99%

Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1

Arita

Isogai

Oda

et al. 2012

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

188

251

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Multiple covalent modifications on a histone tail are often recognized by linked histone reader modules. UHRF1 [ubiquitin-like, containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1], an essential factor for maintenance of DNA methylation, contains linked two-histone reader modules, a tandem Tudor domain and a PHD finger, tethered by a 17-aa linker, and has been implicated to link histone modifications and DNA methylation. Here, we present the crystal structure of the linked histone reader modules of UHRF1 in complex with the amino-terminal tail of histone H3. Our structural and biochemical data provide the basis for combinatorial readout of unmodified Arg-2 (H3-R2) and methylated Lys-9 (H3-K9) by the tandem tudor domain and the PHD finger. The structure reveals that the intermodule linker plays an essential role in the formation of a histone H3-binding hole between the reader modules by making extended contacts with the tandem tudor domain. The histone H3 tail fits into the hole by adopting a compact fold harboring a central helix, which allows both of the reader modules to simultaneously recognize the modification states at H3-R2 and H3-K9. Our data also suggest that phosphorylation of a linker residue can modulate the relative position of the reader modules, thereby altering the histone H3-binding mode. This finding implies that the linker region plays a role as a functional switch of UHRF1 involved in multiple regulatory pathways such as maintenance of DNA methylation and transcriptional repression.epigenetics | multidomain structure | posttranslational modification | X-ray crystallography

show abstract

Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance

Cited by 288 publications

References 54 publications

Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3

Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3

Crystal structure of the human PRMT5:MEP50 complex

Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1

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