HUWE1 plays important role in mouse preimplantation embryo development and the dysregulation is associated with poor embryo development in humans

Chen, L. J.; Xu, Wen-Shan; Yang, Mei; Wang, K.; Chen, Y.; Huang, Xuequan; H., Q.

doi:10.1038/srep37928

Cited by 14 publications

(10 citation statements)

References 22 publications

(38 reference statements)

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“…This is consistent with previous studies observing HUWE1 overexpression in primary tumor samples [94,95]. Interestingly, however, targeted deletion of Huwe1 in some mouse tissues, including keratinocytes, male germ cells, and hematopoietic progenitor cells, has not been found to lead to noticeable p53 activation [90,[188][189][190]. Thus, while promoting the degradation of p53, the role of HUWE1 in cell survival and apoptosis may be context-dependent or tissue-specific.…”

Section: Huwe1supporting

confidence: 91%

Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway

Bang

Kaur

Kurokawa

2019

IJMS

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The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse studies have shown that a genetic defect in the p53 family could lead to spontaneous tumor development, embryonic lethality, or severe tissue abnormality, indicating that the activity of the p53 family must be tightly regulated to maintain normal cellular functions. While the p53 family members are regulated at the level of gene expression as well as post-translational modification, they are also controlled at the level of protein stability through the ubiquitin proteasomal pathway. Over the last 20 years, many ubiquitin E3 ligases have been discovered that directly promote protein degradation of p53, p63, and p73 in vitro and in vivo. Here, we provide an overview of such E3 ligases and discuss their roles and functions.

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Section: Huwe1supporting

confidence: 91%

Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway

Bang

Kaur

Kurokawa

2019

IJMS

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“…The human ubiquitin ligase HUWE1 (also known as ARF-BP1, MULE, LASU1, or HECTH9) regulates the stability of diverse cellular substrates and, in consequence, numerous physiological processes, including DNA replication and damage repair, cell proliferation and differentiation, and apoptosis ( Scheffner and Kumar, 2014 ; Li et al, 2015 ; King et al, 2016 ; Chen et al, 2016 ). HUWE1 is overexpressed in many tumors ( Confalonieri et al, 2009 ; Adhikary et al, 2005 ; Chen et al, 2005 ; Yoon et al, 2005 ; Myant et al, 2016 ) and has been studied intensively in this context.…”

Section: Introductionmentioning

confidence: 99%

A conformational switch regulates the ubiquitin ligase HUWE1

Sander

Eilers

et al. 2017

eLife

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The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues—a mechanism that may be exploited for cancer therapy.DOI: http://dx.doi.org/10.7554/eLife.21036.001

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“…For instance, a remarkable proportion of histone modifiers, zinc fingers and transcriptional factors, and other chromatin-related proteins have been identified. This is the case of the E3 Ubiquitin-Protein Ligase HUWE1 (HUWE1), which has been shown to play an important role in mouse embryo development, and its deregulation in human sperm seems to be associated with poor embryo development (Chen et al 2016). Also, the European sea bass sperm contains the DPY30 homolog isoform 1 (DPY30), a component of the histone methyltransferase complex which is involved in the trimethylation and acetylation of histone H3 (Wang et al 2009;Xu et al 2009;Jiang et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Identification of a complex population of chromatin-associated proteins in the European sea bass (Dicentrarchus labrax) sperm

Barrachina

Anastasiadi

Jodar

et al. 2018

Systems Biology in Reproductive Medicine

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A very common conception about the function of the spermatozoon is that its unique role is to transmit the paternal genome to the next generation. Most of the sperm genome is known to be condensed in many species by protamines, which are small and extremely positively charged proteins (50-70% arginine) with the functions of streamlining the sperm cell and protecting its DNA. However, more recently, it has been shown in mammals that 2-10% of its mature sperm chromatin is also associated to a complex population of histones and chromatin-associated proteins differentially distributed in the genome. These proteins are transferred to the oocyte upon fertilization and may be involved in the epigenetic marking of the paternal genome. However, little information is so far available on the additional potential sperm chromatin proteins present in other protamine-containing non-mammalian vertebrates detected through high-throughput mass spectrometry. Thus, we started the present work with the goal of characterizing the mature sperm proteome of the European sea bass, with a particular focus on the sperm chromatin, chosen as a representative of non-mammalian vertebrate protamine-containing species. Proteins were isolated by acidic extraction from purified sperm cells and from purified sperm nuclei, digested with trypsin, and subsequently the peptides were separated using liquid chromatography and identified through tandem mass spectrometry. A total of 296 proteins were identified. Of interest, the presence of 94 histones and other chromatin-associated proteins was detected, in addition to the protamines. These results provide phylogenetically strategic information, indicating that the coexistence of histones, additional chromatin proteins, and protamines in sperm is not exclusive of mammals, but is also present in other protamine-containing vertebrates. Thus, it indicates that the epigenetic marking of the sperm chromatin, first demonstrated in mammals, could be more fundamental and conserved than previously thought. Abbreviations: AU-PAGE: acetic acid-urea polyacrylamide gel electrophoresis; CPC: chromosomal passenger complex; DTT: dithiothreitol; EGA: embryonic genome activation; FDR: false discovery rate; GO: Gene Ontology; IAA: iodoacetamide; LC: liquid chromatography; LC-MS/MS: liquid chromatography coupled to tandem mass spectrometry; MS: mass spectrometry; MS/MS: tandem mass spectrometry; MW: molecular weight; PAGE: polyacrylamide gel electrophoresis; PBS: phosphate buffered saline; SDS: sodium dodecyl sulfate; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; TCA: trichloroacetic acid.

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HUWE1 plays important role in mouse preimplantation embryo development and the dysregulation is associated with poor embryo development in humans

Cited by 14 publications

References 22 publications

Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway

Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway

A conformational switch regulates the ubiquitin ligase HUWE1

Identification of a complex population of chromatin-associated proteins in the European sea bass (Dicentrarchus labrax) sperm

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