Close encounters of the type III secretion kind

Protein translocation into host epithelial cells by infecting enteropathogenic Escherichia coliWolff, C. et al. (1998)Mol. Microbiol. 28, 143–155The complete sequence of the locus of enterocyte effacement (LEE) from enteropathogenic Escherichia coli E2348/69Elliott, S.J. et al. (1998)Mol. Microbiol. 28, 1–4     

Arabidopsis epigenetics: when RNA meets chromatin

Recent work in plants and other eukaryotes has uncovered a major role for RNA interference in silent chromatin formation. The heritability of the silent state through multiple cell division cycles and, in some instances, through meiosis is assured by epigenetic marks. In plants, transposable elements and transgenes provide striking examples of the stable inheritance of repressed states, and are characterized by dense DNA methylation and heterochromatin histone modifications. Arabidopsis is a useful higher eukaryotes model with which to explore the crossroads between silent chromatin and RNA interference both during development and in the genome-wide control of repeat elements.     

When repair meets chromatin: First in series on chromatin dynamics

In eukaryotic cells, the inheritance of both the DNA sequence and its organization into chromatin is critical to maintain genome stability. This maintenance is challenged by DNA damage. To fully understand how the cell can tolerate genotoxic stress, it is necessary to integrate knowledge of the nature of DNA damage, its detection and its repair within the chromatin environment of a eukaryotic nucleus. The multiplicity of the DNA damage and repair processes, as well as the complex nature of chromatin, have made this issue difficult to tackle. Recent progress in each of these areas enables us to address, both at a molecular and a cellular level, the importance of inter-relationships between them. In this review we revisit the ‘access, repair, restore’ model, which was proposed to explain how the conserved process of nucleotide excision repair operates within chromatin. Recent studies have identified factors potentially involved in this process and permit refinement of the basic model. Drawing on this model, the chromatin alterations likely to be required during other processes of DNA damage repair, particularly double-strand break repair, are discussed and recently identified candidates that might perform such alterations are highlighted.     

Close encounters of the third kind: disordered domains and the interactions of proteins

Protein–protein interactions are thought to be mediated by domains, which are autonomous folding units of proteins. Recently, a second type of interaction has been suggested, mediated by short segments termed linear motifs, which are related to recognition elements of intrinsically disordered regions. Here, we propose a third kind of protein–protein recognition mechanism, mediated by disordered regions longer than 20–30 residues. Bioinformatics predictions and well‐characterized examples, such as the kinase‐inhibitory domain of Cdk inhibitors and the Wiskott–Aldrich syndrome protein (WASP)‐homology domain 2 of actin‐binding proteins, show that these disordered regions conform to the definition of domains rather than motifs, i.e., they represent functional, evolutionary, and structural units. Their functions are distinct from those of short motifs and ordered domains, and establish a third kind of interaction principle. With these points, we argue that these long disordered regions should be recognized as a distinct class of biologically functional protein domains.     

Close encounters of the fatal kind: Landscape features associated with central mountain caribou mortalities

In western Canada, anthropogenic disturbances resulting from resource extraction activities are associated with habitat loss and altered predator–prey dynamics. These habitat changes are linked to increased predation risk and unsustainable mortality rates for caribou (Rangifer tarandus caribou). To inform effective habitat restoration, our goal was to examine whether specific linear disturbance features were associated with caribou predation in central mountain caribou ranges. We used predation‐caused caribou mortalities and caribou GPS‐collar data collected between 2008 and 2015 to assess caribou predation risk within and outside of protected areas at four spatio‐temporal scales: habitat use during the (a) 30 days, (b) 7 days, and (c) 24 hours prior to caribou being killed, and (d) characteristics at caribou kill site locations. Outside of protected areas, predation risk increased closer to pipelines, seismic lines, and streams. Within protected areas, predation risk increased closer to alpine habitat. Factors predicting predation risk differed among spatio‐temporal scales and linear feature types: predation risk increased closer to pipelines during the 30 and 7 days prior to caribou being killed and closer to seismic lines during the 30 days, 7 days, and 24 hours prior, but decreased closer to roads during the 30 days prior to being killed. By assessing habitat use prior to caribou being killed, we identified caribou predation risk factors that would not have been detected by analysis of kill site locations alone. These results provide further evidence that restoration of anthropogenic linear disturbance features should be an immediate priority for caribou recovery in central mountain caribou ranges.     

RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins

Accumulation of repair proteins on damaged chromosomes is required to restore genomic integrity. However, the mechanisms of protein retention at the most destructive chromosomal lesions, the DNA double-strand breaks (DSBs), are poorly understood. We show that RNF8, a RING-finger ubiquitin ligase, rapidly assembles at DSBs via interaction of its FHA domain with the phosphorylated adaptor protein MDC1. This is accompanied by an increase in DSB-associated ubiquitylations and followed by accumulation of 53BP1 and BRCA1 repair proteins. Knockdown of RNF8 or disruption of its FHA or RING domains impaired DSB-associated ubiquitylation and inhibited retention of 53BP1 and BRCA1 at the DSB sites. In addition, we show that RNF8 can ubiquitylate histone H2A and H2AX, and that its depletion sensitizes cells to ionizing radiation. These data suggest that MDC1-mediated and RNF8-executed histone ubiquitylation protects genome integrity by licensing the DSB-flanking chromatin to concentrate repair factors near the DNA lesions.     

Microreview: Innate immune encounters of the (Type) 4th kind: Brucella

In humans, pathogenic Brucella species cause a febrile illness known as brucellosis. A key pathogenic trait of this group of organisms is their ability to survive in immune cells and persist in tissues of the reticuloendothelial system, a process that requires the function of a Type IV secretion system. In contrast to other well‐studied Gram‐negative bacteria, Brucella spp. do not cause inflammation at the site of invasion, but have a latency period of 2–4 weeks before the onset of symptoms. This review discusses several mechanisms that allow Brucella spp. both to evade detection by pattern recognition receptors of the innate immune system and suppress their signalling. In contrast to these stealth features, the VirB Type IV secretion system, which mediates survival within phagocytic cells, stimulates innate immune responses in vivo. The responses stimulated by this virulence factor are sufficient to check bacterial growth, but not to elicit sterilizing immunity. The result is a stand‐off between host and pathogen that results in persistent infection.     

Close encounters of the type‐six kind: injected bacterial toxins modulate gut microbial composition

Bacteria of the phylum Bacteroidetes constitute a substantial portion of the human gut microbiota, including symbionts and opportunistic pathogens. How these bacteria coexist and provide colonization resistance to pathogenic strains is not well understood. In this issue of EMBO Reports, Hecht and colleagues describe a mechanism by which strains of Bacteroides fragilis compete with each other for an intestinal niche 1 . Prompted by the observation that B. fragilis populations appear to be dominated by either commensal, non‐toxigenic strains, or by enterotoxigenic, potentially pathogenic strains, the authors investigated mechanisms of competition between these two subsets. In agreement with two recent studies 2 3 , Hecht et al 1 found that competition between B. fragilis strains is dependent on a type‐6 secretion system (T6SS) apparatus, secreted effectors, and immunity genes. They identify a T6SS effector–immunity gene pair that enables a non‐toxigenic strain to competitively exclude enterotoxigenic B. fragilis, thus providing a proof of principle for the use of T6SS‐mediated killing as a therapeutic strategy to eradicate pathogenic strains.     

Close encounters of the worst kind: reforms needed to curb coral reef damage by recreational divers

Coral Reefs - Intentional and unintentional physical contact between scuba divers and the seabed is made by most divers and multiple times per dive, which often results in damage to corals and...     

RNF8-dependent and RNF8-independent regulation of 53BP1 in response to DNA damage

The DNA damage surveillance network orchestrates cellular responses to DNA damage through the recruitment of DNA damage-signaling molecules to DNA damage sites and the concomitant activation of protein phosphorylation cascades controlled by the ATM (ataxia-telangiectasia-mutated) and ATR (ATM-Rad3-related) kinases. Activation of ATM/ATR triggers cell cycle checkpoint activation and adaptive responses to DNA damage. Recent studies suggest that protein ubiquitylation or degradation plays an important role in the DNA damage response. In this study, we examined the potential role of the proteasome in checkpoint activation and ATM/ATR signaling in response to UV light-induced DNA damage. HeLa cells treated with the proteasome inhibitor MG-132 showed delayed phosphorylation of ATM substrates in response to UV light. UV light-induced phosphorylation of 53BP1, as well as its recruitment to DNA damage foci, was strongly suppressed by proteasome inhibition, whereas the recruitment of upstream regulators of 53BP1, including MDC1 and H2AX, was unaffected. The ubiquitin-protein isopeptide ligase RNF8 was critical for 53BP1 focus targeting and phosphorylation in ionizing radiation-damaged cells, whereas UV light-induced 53BP1 phosphorylation and targeting exhibited partial dependence on RNF8 and the ubiquitin-conjugating enzyme UBC13. Suppression of RNF8 or UBC13 also led to subtle defects in UV light-induced G2/M checkpoint activation. These findings are consistent with a model in which RNF8 ubiquitylation pathways are essential for 53BP1 regulation in response to ionizing radiation, whereas RNF8-independent pathways contribute to 53BP1 targeting and phosphorylation in response to UV light and potentially other forms of DNA replication stress.     

X-inactivation: close encounters of the X kind

X chromosome inactivation ensures equal dosage of X-linked genes between male and female mammals. Two new studies have shown that the initiation of inactivation is preceded by X chromosome pairing; their results implicate this pairing in the choice and counting functions of X chromosome inactivation.     

BCL10 regulates RNF8/RNF168-mediated ubiquitination in the DNA damage response

Timely and proper cellular response to DNA damage is essential for maintenance of genome stability and integrity. B-cell lymphoma/leukemia 10 (BCL10) facilitates ubiquitination of NEMO in the cytosol, activating NFκB signaling. Translocation and/or point mutations of BCL10 associate with mucosa-associated lymphoid tissue lymphomas and other malignancies. However, the mechanisms by which the resulting aberrant expression of BCL10 leads to cellular oncogenesis are poorly understood. In this report, we found that BCL10 in the nucleus is enriched at the DNA damage sites in an ATM- and RNF8-dependent manner. ATM-dependent phosphorylation of BCL10 promotes its interaction with and presentation of UBC13 to RNF8, and RNF8-mediated ubiquitination of BCL10 enhances binding of BCL10 and UBC13 to RNF168. This allows mono-ubiquitination on H2AX by RNF168 and further poly-ubiquitination by the RNF8/RNF168-containing complex. Depletion of BCL10 compromised homology recombination-mediated DNA double-strand break (DSB) repair because of insufficient recruitment of BRCA1, RAD51, and the ubiquitinated DNA damage response factors. Taken together, our results demonstrate a novel function of BCL10 in delivering UBC13 to RNF8/RNF168 to regulate ubiquitination-mediated DSB signaling and repair.     

RNF8/RNF168信号通路在DNA损伤修复中的作用

细胞内DNA会受部分外界因素(如紫外辐射,电离辐射和化学毒素)和内部因素(如复制错误)的影响而发生损伤,包括DNA双链断裂、DNA错配和DNA交链等。DNA损伤发生后,损伤部位会被一些蛋白识别,进而招募一系列蛋白至损伤部位,形成一个修复系统。DNA双链断裂是最严重的一种DNA损伤,错误修复往往导致疾病的发生。DNA双链断裂(double strand break, DSB)后,细胞启动RNF8/RNF168信号通路进行修复。RNF8和RNF168是这条通路的枢纽蛋白;53BP和BRCA1是关键的效应蛋白,决定着DSB修复的方式;组蛋白泛素化、磷酸化和甲基化等翻译后修饰是这条通路顺利进行的基本条件;染色质重塑、泛素化酶/去泛素化酶平衡和蛋白稳定性是这条通路的主要调节方式。本综述对RNF8/RNF168信号通路进行了梳理总结,希望其能对相关研究者起到参考作用。     

Prion disease: close encounters of the cellular kind

Co-culture of prion-infected cells with uninfected target cells has recently been found to lead to rapid and efficient transmission of infectivity to the target cells by a process that is dependent on direct cell contact.