TDRD3 Is an Effector Molecule for Arginine-Methylated Histone Marks

Yang, Yanzhong; Lu, Yue; Espejo, Alexsandra; Wu, Jianpeng; Xu, Wei; Liang, Shoudan; Bedford, Mark T.

doi:10.1016/j.molcel.2010.11.024

Cited by 196 publications

(214 citation statements)

References 34 publications

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“…[35][36][37] H3R17me2as is generally an activating mark. 38,39 Interestingly, there was a differential enrichment of these three histone marks, since H3R2me2 and H3R17me2 are abundantly expressed in the cap mesenchyme and nascent nephrons, whereas H3R8me2 is more enriched in nascent nephrons (Fig. 10A-C).…”

Section: Histone Methylation Of Arginine 2 8 and 17 Of Histonementioning

confidence: 98%

In situ histone landscape of nephrogenesis

et al. 2013

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Section: Histone Methylation Of Arginine 2 8 and 17 Of Histonementioning

confidence: 98%

In situ histone landscape of nephrogenesis

et al. 2013

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“…array platform developed to identify protein domains that bind to modified peptides, and includes a large number of reader domains involved with chromatin and transcriptional control (10). We identified a "hit" protein in the screen, the tandem tudor protein 53BP1, which bound to the methylated, but not unmethylated, pRb peptide (Fig.…”

Section: Significancementioning

confidence: 99%

Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor

Carr

Munro

Zalmas

et al. 2014

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

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The retinoblastoma tumor suppressor protein pRb is a key regulator of cell cycle progression and mediator of the DNA damage response. Lysine methylation at K810, which occurs within a critical Cdk phosphorylation motif, holds pRb in the hypophosphorylated growth-suppressing state. We show here that methyl K810 is read by the tandem tudor domain containing tumor protein p53 binding protein 1 (53BP1). Structural elucidation of 53BP1 in complex with a methylated K810 pRb peptide emphasized the role of the 53BP1 tandem tudor domain in recognition of the methylated lysine and surrounding residues. Significantly, binding of 53BP1 to methyl K810 occurs on E2 promoter binding factor target genes and allows pRb activity to be effectively integrated with the DNA damage response. Our results widen the repertoire of cellular targets for 53BP1 and suggest a previously unidentified role for 53BP1 in regulating pRb tumor suppressor activity.T he retinoblastoma tumor suppressor protein pRb is either directly mutated or functionally inactivated in the vast majority of human tumors (1). One of its principle roles in cells is to regulate transcription, and the E2 promoter binding factor (E2F) family of transcription factors represents one of its most important targets (2). E2F acts to regulate the expression of a variety of genes connected with cell cycle progression and cell fate (including apoptosis, senescence, and differentiation), and the physical interaction between pRb and E2F hinders transcriptional activation by E2F, which coincides with cell cycle arrest (2, 3).The tumor suppressor activity of pRb and its interaction with E2F is regulated by posttranslational modifications (4). For example, multiple cyclin-dependent kinase (Cdk) phosphorylation events occur within pRb, and pRb phosphorylation is temporally regulated as cells progress through the cell cycle, which disrupts the interaction between pRb and E2F. Other types of modification, such as acetylation in the C-terminal region, are also known to influence pRb activity (5).More recently, a role for lysine (K) methylation in pRb control has been described (6). Thus, residue K810 undergoes methylation mediated by SET [su(var), enhancer-of-zeste, trithorax] domain containing lysine methyltransferase 7 (Set7/9) (also known as SETD7/KMT7) (6). Monomethylation at K810 holds pRb in the hypophosphorylated growth suppressing state, which occurs at a mechanistic level by inhibiting the physical association of Cdk complexes with pRb and thereby blocks Cdk-dependent phosphorylation (6). This is because, in the unmethylated state, K810 acts as the essential basic residue in the Cdk consensus phosphorylation site S807 (namely SPLK, Fig. 1A), which is an early pRb phosphorylation event during cell cycle control (7). Significantly, methylation of K810 hinders recognition and subsequent phosphorylation of S807 by cyclin/ Cdk complexes (6).Here, we have elucidated a previously unidentified level of regulation imposed on pRb mediated by the methylation event at K810. In addition to inhi...

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“…The recently identified H3R17me2a effector molecule TDRD3 was also found to interact with H4R3me2a, a site modified by PRMT1 on histone H4 (10). To investigate if PAF1c interacts with the PRMT1-modified histone mark, we reconstituted histone octamers from bacterially expressed core histones ( Fig.…”

Section: Identification Of Human Paf1c As a Binding Partner For The Hmentioning

confidence: 99%

“…PAF1c subunits are nuclear proteins directly associated with RNAPII and can regulate multiple steps of transcription. Recently, TDRD3 was found to bind both the H3R17me2a and H4R3me2a marks (10). It is plausible that multiple effector proteins exist for the H3R17me2a mark that direct this mark to divergent biological processes.…”

Section: Paf1c and Carm1 Coordinately Regulate A Common Set Of Erαmentioning

confidence: 99%

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Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

2012

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

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The histone coactivator-associated arginine methyltransferase 1 (CARM1) is a coactivator for a number of transcription factors, including nuclear receptors. Although CARM1 and its asymmetrically deposited dimethylation at histone H3 arginine 17 (H3R17me2a) are associated with transcription activation, the mechanism by which CARM1 activates transcription remains unclear. Using an unbiased biochemical approach, we discovered that the transcription elongation-associated PAF1 complex (PAF1c) directly interacts with H3R17me2a. PAF1c binds to histone H3 tails harboring dimethylation at R17 in CARM1-methylated histone octamers. Knockdown of either PAF1c subunits or CARM1 affected transcription of CARM1-regulated, estrogen-responsive genes. Furthermore, either CARM1 knockdown or CARM1 enzyme-deficient mutant knockin resulted in decreased H3R17me2a accompanied by the reduction of PAF1c occupancy at the proximal promoter estrogen-responsive elements. In contrast, PAF1c knockdown elicited no effects on H3R17me2a but reduced the H3K4me3 level at estrogen-responsive elements. These observations suggest that, apart from PAF1c's established roles in directing histone modifications, PAF1c acts as an arginine methyl histone effector that is recruited to promoters and activates a subset of genes, including targets of estrogen signaling.estrogen receptor-α | histone arginine methylation | PRMT

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TDRD3 Is an Effector Molecule for Arginine-Methylated Histone Marks

Cited by 196 publications

References 34 publications

In situ histone landscape of nephrogenesis

In situ histone landscape of nephrogenesis

Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

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