Cooperative DNA and histone binding by Uhrf2 links the two major repressive epigenetic pathways

Pichler, Garwin; Wolf, Patricia; Schmidt, Christine S.; Meilinger, Daniela; Schneider, Katja; Frauer, Carina; Fellinger, Karin; Rottach, Andrea; Leonhardt, Heinrich

doi:10.1002/jcb.23185

Cited by 68 publications

(103 citation statements)

References 49 publications

(66 reference statements)

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“…The UHRF2 protein can bind methylated DNA through its SRA domain and H3K9me3 through its TTD-PHD region (Fournier et al, 2011;Parry et al, 2011;Pichler et al, 2011). These processes are important for UHRF2 to be involved in controlling the expression of multiple genes through chromatin and transcriptional regulation (Zhang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

UHRF2 mRNA Expression is Low in Malignant Glioma but Silencing Inhibits the Growth of U251 Glioma Cells in vitro

Zhang²,

Su³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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UHRF2 is a member of the ubiquitin plant homeo domain RING finger family, which has been proven to be frequently up-regulated in colorectal cancer cells and play a role as an oncogene in breast cancer cells. However, the role of UHRF2 in glioma cells remains unclear. In this study, we performed real-time quantitative PCR on 32 pathologically confirmed glioma samples (grade I, 4 cases; grade II, 11 cases; grade III, 10 cases; and grade IV, 7 cases; according to the 2007 WHO classification system) and four glioma cell lines (A172, U251, U373, and U87). The expression of UHRF2 mRNA was significantly lower in the grade III and grade IV groups compared with the noncancerous brain tissue group, whereas its expression was high in A172, U251, and U373 glioma cell lines. An in vitro assay was performed to investigate the functions of UHRF2. Using a lentivirus-based RNA interference (RNAi) approach, we down-regulated UHRF2 expression in the U251 glioma cell line. This downregulation led to the inhibition of cell proliferation, an increase in cell apoptosis, and a change of cell cycle distribution, in which S stage cells decreased and G2/M stage cells increased. Our results suggest that UHRF2 may be closely related to tumorigenesis and the development of gliomas.

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Section: Discussionmentioning

confidence: 99%

UHRF2 mRNA Expression is Low in Malignant Glioma but Silencing Inhibits the Growth of U251 Glioma Cells in vitro

Zhang²,

Su³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…UHRF1 null mouse embryos display a severe DNA methylation defect, similar to DNMT1 nulls (42,43). Intriguingly, ectopic expression of UHRF2 does not rescue this UHRF1 null defect, nor does UHRF2 display preferential binding to hemi-methylated DNA over unmethylated DNA as UHRF1, suggesting distinct functions between these proteins (18,19).…”

Section: Figure 9 E2f1 and Uhrf2 Bind To Co-regulated Targets By Chimentioning

confidence: 96%

“…Both UHRF1 and UHRF2 contain LXCXE motifs in their PHD domain and physically associate with the pRB protein (20,21). The SRA domain of UHRF1 preferentially recognizes and binds to hemimethylated DNA, although the UHRF2 SRA domain shows no apparent distinction in binding between hemi-over unmethylated DNA (18).…”

Section: Figure 9 E2f1 and Uhrf2 Bind To Co-regulated Targets By Chimentioning

confidence: 99%

“…UHRF2 contains a ubiquitin-like domain, PHD finger domain, a set-and ringassociated (SRA) domain, and a RING finger domain (17). UHRF2 is functionally distinct from the structurally similar UHRF1, as ectopic UHRF2 expression does not rescue the DNA methylation defect in UHRF1 null mouse embryonic stem cells (18,19). Intriguingly, both UHRF2 and UHRF1 physically associate with the Rb tumor suppressor protein and appear to recognize DNA and histone methylation to control cell cycle progression and gene expression (20,21).…”

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The Nuclear Protein UHRF2 Is a Direct Target of the Transcription Factor E2F1 in the Induction of Apoptosis

Lü

Hallstrom

2013

Journal of Biological Chemistry

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Background: E2F1-induced apoptosis kills oncogene-stressed cells, and regulators of this process may act as tumor suppressors. Results: We identified UHRF2 in a functional screen for mediators of E2F1 induced apoptosis. Conclusion: UHRF2 binds directly to E2F1 and is required for E2F1 induction of apoptosis and expression of several important apoptosis inducers. Significance: UHRF2 is a suspected tumor suppressor and our work suggests an anti-tumor mechanism.

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“…Uhrf1 knockout mice is embryonic lethal and Uhrf1 knock-out ES cells have dramatic decrease in global DNA methylation (27,28), suggesting that UHRF1 and UHRF2 are not functionally redundant in the maintenance of DNA methylation. UHRF1 is highly expressed in undifferentiated cells while the expression of UHRF2 is low in undifferentiated cells and increases when cells are differentiated (29). Although both UHRF1 and UHRF2 interact with DNMT1, UHRF2 cannot target DNMT1 to pericentric heterochromatin (PCH) in S phase when overexpressed in cells (30).…”

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confidence: 99%

Zinc Finger Protein 618 Regulates the Function of UHRF2 (Ubiquitin-like with PHD and Ring Finger Domains 2) as a Specific 5-Hydroxymethylcytosine Reader

Liu

Zhang

Kuang

et al. 2016

Journal of Biological Chemistry

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5-Hydroxymethylcytosine (5hmC) is an epigenetic modification that is generated by ten-eleven translocation (TET) protein-mediated oxidation of 5-methylcytosine (5mC). 5hmC is associated with transcription regulation and is decreased in many cancers including melanoma. Accumulating evidence has suggested that 5hmC is functionally distinct from 5mC. Ubiquitin-like with PHD and ring finger domains 2 (UHRF2) is the first known specific 5hmC reader that has higher affinity to 5hmC than 5mC, suggesting that UHRF2 might mediate 5hmC's function. Structural analysis has revealed the molecular mechanism of UHRF2-5hmC binding in vitro, but it is not clear how UHRF2 recognizes 5hmC in vivo. In this study, we have identified zinc figure protein 618 (ZNF618) as a novel binding partner of UHRF2. ZNF618 specifically interacts with UHRF2 but not its paralog UHRF1. Importantly, ZNF618 co-localizes with UHRF2 at genomic loci that are enriched for 5hmC. The ZNF618 chromatin localization is independent of its interaction with UHRF2 and is through its first two zinc fingers. Instead, ZNF618 regulates UHRF2 chromatin localization. Collectively, our study suggests that ZNF618 is a key protein that regulates UHRF2 function as a specific 5hmC reader in vivo.DNA methylation is an epigenetic modification that regulates multiple cellular processes including gene transcription, genomic imprinting, and X chromosome inactivation. DNA methylation mainly exists as 5-methylcytosine (5mC) 3 in CpG context, which is established and maintained by three major DNA methyltransferases in cells (1). 5mC can be oxidized by ten-eleven translocation (TET) proteins to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) (2-4). These 5mC derivatives are believed to be intermediates of DNA demethylation (5).5hmC is much more abundant than others among three 5mC derivatives (6). It is not a favorable substrate for further oxidation and is therefore most stable (7,8). It is widely present in many cell types and tissues and is particularly enriched in neurons and stem cells (9, 10). 5hmC and 5mC have different genome-wide distributions and are associated with different transcriptional outcome (11-16). Loss of 5hmC, but not 5mC, is a hallmark of many cancers including melanoma (17). These studies suggest that 5hmC is more than just an intermediate of DNA demethylation, but is an important epigenetic modification that is distinct from 5mC.The function of 5hmC is still not clear, largely due to the lack of knowledge about 5hmC readers. Previous studies have shown that some 5mC readers, such as UHRF1 and MeCP2, can also bind 5hmC (18,19). These proteins use the same 5mC-binding domain to interact with 5hmC, but the 5hmC binding affinity was similar to or weaker than their 5mC binding affinities (18,19). Recent proteomic approaches have revealed several 5hmC-specific binding proteins that have higher affinity to 5hmC than 5mC (20). UHRF2 is the best characterized one and its SRA domain has 3-fold higher binding affinity to 5hmC than 5m...

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Cooperative DNA and histone binding by Uhrf2 links the two major repressive epigenetic pathways

Cited by 68 publications

References 49 publications

UHRF2 mRNA Expression is Low in Malignant Glioma but Silencing Inhibits the Growth of U251 Glioma Cells in vitro

UHRF2 mRNA Expression is Low in Malignant Glioma but Silencing Inhibits the Growth of U251 Glioma Cells in vitro

The Nuclear Protein UHRF2 Is a Direct Target of the Transcription Factor E2F1 in the Induction of Apoptosis

Zinc Finger Protein 618 Regulates the Function of UHRF2 (Ubiquitin-like with PHD and Ring Finger Domains 2) as a Specific 5-Hydroxymethylcytosine Reader

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