journal article
Open Access Collection
Home
doi: 10.1038/embor.2009.229pmid: 19881530
Steven Rose makes his case for an academic boycott of Israel in response to the situation of Palestinian scientists.
Cyr, Douglas M.; Hebert, Daniel N.
doi: 10.1038/embor.2009.224pmid: 19851332
The proper folding of proteins is essential for cellular homeostasis and prevention of an ever‐growing number of diseases. Here, the authors highlight recent breakthroughs in the study of the unfolded protein response and new strategies to combat the diseases caused by its malfunction.
Hjerpe, Roland; Aillet, Fabienne; Lopitz‐Otsoa, Fernando; Lang, Valerie; England, Patrick; Rodriguez, Manuel S
doi: 10.1038/embor.2009.192pmid: 19798103
Post‐translational modification with ubiquitin is one of the most important mechanisms in the regulation of protein stability and function. However, the high reversibility of this modification is the main obstacle for the isolation and characterization of ubiquitylated proteins. To overcome this problem, we have developed tandem‐repeated ubiquitin‐binding entities (TUBEs) based on ubiquitin‐associated (UBA) domains. TUBEs recognize tetra‐ubiquitin with a markedly higher affinity than single UBA domains, allowing poly‐ubiquitylated proteins to be efficiently purified from cell extracts in native conditions. More significant is the fact that TUBEs protect poly‐ubiquitin‐conjugated proteins, such as p53 and IκBα, both from proteasomal degradation and de‐ubiquitylating activity present in cell extracts, as well as from existing proteasome and cysteine protease inhibitors. Therefore, these new ‘molecular traps’ should become valuable tools for purifying endogenous poly‐ubiquitylated proteins, thus contributing to a better characterization of many essential functions regulated by these post‐translational modifications.
doi: 10.1038/embor.2009.221pmid: 19834511
The regulation of gene expression programmes is essential for the generation of diverse cell types during development and for adaptation to environmental signals. RNA polymerase II (RNAPII) transcribes genetic information and coordinates the recruitment of accessory proteins that are responsible for the establishment of active chromatin states and transcript maturation. RNAPII is post‐translationally modified at active genes during transcription initiation, elongation and termination, and thereby recruits specific histone and RNA modifiers. RNAPII complexes are also located at silent genes in promoter‐proximal paused configurations that provide dynamic transcriptional regulation downstream from initiation. In embryonic stem cells, silent developmental regulator genes that are repressed by Polycomb are associated with a form of RNAPII that can elongate through coding regions but that lacks the post‐translational modifications that are important for coupling RNA synthesis to co‐transcriptional maturation. Here, we discuss the mechanisms through which the transcription of silent genes might be dissociated from productive expression, and the sophisticated interplay between the transcriptional machinery, Polycomb repression and RNA processing.
Meilinger, Daniela; Fellinger, Karin; Bultmann, Sebastian; Rothbauer, Ulrich; Bonapace, Ian Marc; Klinkert, Wolfgang E F; Spada, Fabio; Leonhardt, Heinrich
doi: 10.1038/embor.2009.201pmid: 19798101
Recent studies have indicated that nuclear protein of 95 kDa (Np95) is essential for maintaining genomic methylation by recruiting DNA methyltransferase (Dnmt) 1 to hemi‐methylated sites. Here, we show that Np95 interacts more strongly with regulatory domains of the de novo methyltransferases Dnmt3a and Dnmt3b. To investigate possible functions, we developed an epigenetic silencing assay using fluorescent reporters in embryonic stem cells (ESCs). Interestingly, silencing of the cytomegalovirus promoter in ESCs preceded DNA methylation and was strictly dependent on the presence of either Np95, histone H3 methyltransferase G9a or Dnmt3a and Dnmt3b. Our results indicate a regulatory role for Np95, Dnmt3a and Dnmt3b in mediating epigenetic silencing through histone modification followed by DNA methylation.
doi: 10.1038/embor.2009.231pmid: 19834508
V‐ATPases acidify intracellular compartments and the intercellular matrix and are essential for life. They are implicated in various diseases and structural information is crucial. The elucidation of its structure by Numoto et al. will provide insights into its function and aid in drug design.
Wang, Jingxin; Jacob, Naduparambil K; Ladner, Katherine J; Beg, Amer; Perko, James D; Tanner, Stephan M; Liyanarachchi, Sandya; Fishel, Richard; Guttridge, Denis C
doi: 10.1038/embor.2009.197pmid: 19779484
Nuclear factor (NF)‐κB is a positive regulator of tumour development and progression, but how it functions in normal cells leading to oncogenesis is not clear. As cellular senescence has proven to be an intrinsic tumour suppressor mechanism that cells must overcome to establish deregulated growth, we used primary fibroblasts to follow NF‐κB function in cells transitioning from senescence to subsequent immortalization. Our findings show that RelA/p65−/− murine fibroblasts immortalize at considerably faster rates than RelA/p65+/+ cells. The ability of RelA/p65−/− fibroblasts to escape senescence earlier is due to their genomic instability, characterized by high frequencies of DNA mutations, gene deletions and gross chromosomal translocations. This increase in genomic instability is closely related to a compromised DNA repair that occurs in both murine RelA/p65−/− fibroblasts and tissues. Significantly, these results can also be duplicated in human fibroblasts lacking NF‐κB. Altogether, our findings present a fresh perspective on the role of NF‐κB as a tumour suppressor, which acts in pre‐neoplastic cells to maintain cellular senescence by promoting DNA repair and genomic stability.
Ploss, Alexander; Rice, Charles M.
doi: 10.1038/embor.2009.223pmid: 19834510
Hepatitis C virus (HCV) causes chronic liver disease and affects an estimated 3% of the world's population. Options for the prevention or therapy of HCV infection are limited; there is no vaccine and the nonspecific, interferon‐based treatments now in use are frequently ineffective and have significant side effects. A small‐animal model for HCV infection would significantly expedite antiviral compound development and preclinical testing, as well as open new avenues to decipher the mechanisms that underlie viral pathogenesis. The natural species tropism of HCV is, however, limited to humans and chimpanzees. Here, we discuss the prospects of developing a mouse model for HCV infection, taking into consideration recent results on HCV entry and replication, and new prospects in xenotransplantation biology. We highlight three independent, but possibly complementary, approaches towards overcoming current species barriers and generating a small‐animal model for HCV pathogenesis.
Otani, Junji; Nankumo, Toshiyuki; Arita, Kyohei; Inamoto, Susumu; Ariyoshi, Mariko; Shirakawa, Masahiro
doi: 10.1038/embor.2009.218pmid: 19834512
DNMT3 proteins are de novo DNA methyltransferases that are responsible for the establishment of DNA methylation patterns in mammalian genomes. Here, we have determined the crystal structures of the ATRX–DNMT3–DNMT3L (ADD) domain of DNMT3A in an unliganded form and in a complex with the amino‐terminal tail of histone H3. Combined with the results of biochemical analysis, the complex structure indicates that DNMT3A recognizes the unmethylated state of lysine 4 in histone H3. This finding indicates that the recruitment of DNMT3A onto chromatin, and thereby de novo DNA methylation, is mediated by recognition of the histone modification state by its ADD domain. Furthermore, our biochemical and nuclear magnetic resonance data show mutually exclusive binding of the ADD domain of DNMT3A and the chromodomain of heterochromatin protein 1α to the H3 tail. These results indicate that de novo DNA methylation by DNMT3A requires the alteration of chromatin structure.
Showing 1 to 10 of 21 Articles