Structure and function of the nucleosome-binding PWWP domain

Su, Qin; Min, Jinrong

doi:10.1016/j.tibs.2014.09.001

Cited by 176 publications

(141 citation statements)

References 82 publications

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“…However, based on the proximity of the histone H3 Lys-36 residue to the nucleosome core, recognition of H3K36 modifications by reader domains may be influenced by structural components of the core. Indeed, the majority of H3K36me3 reader domains show stronger binding to substrates comprising both the histone modification and DNA (such as nucleosomes) than to the modification alone (30). We therefore reasoned that any potential H3K36me2-specific binding domain would likely also require reading the modification in a nucleosomal context.…”

Section: Resultsmentioning

confidence: 99%

A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin

Sankaran¹,

Wilkinson²,

Elias

et al. 2016

Journal of Biological Chemistry

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The readout of histone modifications plays a critical role in chromatin-regulated processes. Dimethylation at Lys-36 on histone H3 (H3K36me2) is associated with actively transcribed genes, and global up-regulation of this modification is associated with several cancers. However, the molecular mechanism by which H3K36me2 is sensed and transduced to downstream biological outcomes remains unclear. Here we identify a PWWP domain within the histone lysine methyltransferase and oncoprotein NSD2 that preferentially binds to nucleosomes containing H3K36me2. In cells, the NSD2 PWWP domain interaction with H3K36me2 plays a role in stabilizing NSD2 at chromatin. Furthermore, NSD2's ability to induce global increases in H3K36me2 via its enzymatic activity, and consequently promote cellular proliferation, is compromised by mutations within the PWWP domain that specifically abrogate H3K36me2-recognition. Together, our results identify a pivotal role for NSD2 binding to its catalytic product in regulating its cellular functions, and suggest a model for how this interaction may facilitate epigenetic spreading and propagation of H3K36me2.Chromatin dynamics play a critical role in the regulation of diverse cellular functions, the dysregulation of which is linked to the development and progression of human diseases. A major mechanism for regulating chromatin functional states involves the reversible covalent post-translational modification of histone proteins by chemical moieties such as methyl-, acetyl-, and phospho-groups. Histones provide a highly modifiable signaling surface on which these chemical marks combine to define particular chromatin states and regulate the extent of accessibility of DNA to trans-acting factors. In this context, the proteins and domains that recognize histone modification fundamentally influence DNA-templated processes, transducing molecular events at chromatin to biological outcomes. Protein lysine methylation is a principal chromatin-regulatory mechanism. The chemical addition of methyl moieties to lysine residues is catalyzed by lysine methyltransferases (KMTs).3 Lysine residues can accept up to three methyl groups forming mono-, di-, and tri-methylated derivatives (referred to as me1, me2, and me3, respectively). Histone methylation has been linked via methyllysine-binding proteins to diverse processes, including transcription, DNA recombination, DNA repair, and DNA replication.Methylation of histone H3 at lysine 36 (H3K36) is found at gene bodies of actively transcribed genes, but the state of methylation at this residue defines distinct biological outcomes. Trimethylation of this site (H3K36me3), which is mediated by the KMT SETD2 in humans, is involved in splicing regulation, RNA processing, and DNA damage signaling (1-7). Loss of SETD2 and H3K36me3 is a recurring phenomenon in clear cell renal cell carcinoma (ccRCC) and other cancers, suggesting a tumor suppressor role for SETD2 (8 -10). In contrast, the specific molecular functions associated with H3K36me2 are unclear. However, elevated level...

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Section: Resultsmentioning

confidence: 99%

A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin

Sankaran¹,

Wilkinson²,

Elias

et al. 2016

Journal of Biological Chemistry

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“…The PWWP domain often involves chromatin‐associated biological processes (Qin and Min, 2014). The PWWP domain was first characterized from the WHSC1 (Wolf–Hirschhorn syndrome candidate 1) gene and was previously known as the HATH domain (Bao et al ., 2014b).…”

Section: Discussionmentioning

confidence: 99%

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

et al. 2018

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Although identified as a growth factor, the mechanism by which hepatoma‐derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA‐sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF‐induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor. Coexpression of SREBP‐1 and nuclear HDGF predicts poor prognosis for HCC. In addition, by changing the first amino acid of the PWWP domain from proline to alanine, the type of PWWP domain changed from P‐ to A‐type, resulting in inability to induce SREBP‐1‐mediated gene transcription. The type of PWWP domain affects the recruitment of the C‐terminal binding protein‐1 transcriptional repressor on the promoter of the lipogenic gene. Our data indicate that HDGF acts as a coactivator of SREBP1‐mediated transcription of lipogenic genes. The PWWP domain is crucial for HDGF to promote lipogenesis. Moreover, transcriptional regulation of nuclear HDGF plays important roles in the development of HCC.

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“…A number of domains bind methylated histone tails. Prominent examples include the chromodomain, Tudor domain, MBT domain, PWWP domain, and PHD domain (4,6,7). The CW domain has recently been identified as a new member of the lysine methylation reader family (8 -11).…”

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confidence: 99%

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

Liu

Tempel

Zhang

et al. 2016

Journal of Biological Chemistry

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Covalent modifications of histone N-terminal tails play a critical role in regulating chromatin structure and controlling gene expression. These modifications are controlled by histone-modifying enzymes and read out by histone-binding proteins. Numerous proteins have been identified as histone modification readers. Here we report the family-wide characterization of histone binding abilities of human CW domain-containing proteins. We demonstrate that the CW domains in ZCWPW2 and MORC3/4 selectively recognize histone H3 trimethylated at Lys-4, similar to ZCWPW1 reported previously, while the MORC1/2 and LSD2 lack histone H3 Lys-4 binding ability. Our crystal structures of the CW domains of ZCWPW2 and MORC3 in complex with the histone H3 trimethylated at Lys-4 peptide reveal the molecular basis of this interaction. In each complex, two tryptophan residues in the CW domain form the "floor" and "right wall," respectively, of the methyllysine recognition cage. Our mutation results based on ZCWPW2 reveal that the right wall tryptophan residue is essential for binding, and the floor tryptophan residue enhances binding affinity. Our structural and mutational analysis highlights the conserved roles of the cage residues of CW domain across the histone methyllysine binders but also suggests why some CW domains lack histone binding ability.Chromatin structure is dynamically regulated by histone post-translational modifications, such as methylation, acetylation, phosphorylation, ubiquitination, and sumoylation (1). These post-translational modifications constitute the "histone code," which is written or erased by histone-modifying enzymes and recognized by histone code "reader" proteins (2-4).Histone methylation, such as lysine methylation at the ⑀-amino group at levels from mono-to trimethylation (me1-me3), has received extensive attention (5). A number of domains bind methylated histone tails. Prominent examples include the chromodomain, Tudor domain, MBT domain, PWWP domain, and PHD domain (4, 6, 7). The CW domain has recently been identified as a new member of the lysine methylation reader family (8 -11).The CW domain is a zinc binding domain, composed of ϳ50 amino acid residues with four conserved cysteine (C) and two conserved tryptophan (W) residues, and its name was derived from these conserved residues. CW domains are found in chromatin-associated proteins in animals and plants and grouped into 12 families based on sequence similarity (12). There are seven CW domain-containing proteins in humans, namely ZCWPW1, ZCWPW2, MORC1, MORC2, MORC3, MORC4, and LSD2 (Fig. 1A). Prior studies have shown that the CW domains of ZCWPW1 (8), MORC3 (10), and MORC4 (9) are readers of H3K4 3 methylated histones with differing preferences for histone H3K4 methylation states (i.e. ZCWPW1 and MORC3 preferentially recognize histone H3K4me3 (8, 10), whereas the CW domain of human MORC4 prefers dimethylated H3K4 (9)). The LSD2 CW domain is required for the demethylation function of LSD2 but does not bind to any H3K4 peptides (13). However, th...

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Structure and function of the nucleosome-binding PWWP domain

Cited by 176 publications

References 82 publications

A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin

A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

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