Hepatitis C-associated liver carcinogenesis:Role of PML nuclear bodies

Successful escape from immune response characterises chronic hepatitis C virus (HCV) infection, which results in persistence of infection in about 80% of the patients. The deleterious consequences are cirrhosis and hepatocellular carcinoma. HCV accounts the most frequent cause for hepatocellular carcinoma (HCC) and liver transplantation (LT) in the western world. The underlying molecular mechanisms how HCV promotes tumor development are largely unknown. There is some in vitro and in vivo evidence that HCV interferes with the tumor suppressor PML and may thereby importantly contribute to the HCV-associated pathogenesis with respect to the development of HCC. The tumor suppressor protein “promyelocytic leukemia” (PML) has been implicated in the regulation of important cellular processes like differentiation and apoptosis. In cancer biology, PML and its associated nuclear bodies (NBs) have initially attracted intense interest due to its role in the pathogenesis of acute promyelocytic leukemia (APL). More recently, loss of PML has been implicated in human cancers of various histologic origins. Moreover, number and intensity of PML-NBs increase in response to interferons (IFNs) and there is evidence that PML-NBs may represent preferential targets in viral infections. Thus, PML could not only play a role in the mechanisms of the antiviral action of IFNs but may also be involved in a direct oncogenic effect of the HCV on hepatocytes. This review aims to summarise current knowledge about HCV-related liver carcinogenesis and to discuss a potential role of the nuclear body protein PML for this this hard-to-treat cancer.

ON THE HYPERSPHERICAL HARMONIC METHODTO THREE AND FOUR BODY NUCLEAR PROBLEMS

In this paper, the hyperspherical harmonics used for solving the three and four body problems in nuclear physics are given. The equations of the adiabatic approximation to hyperspherical harmonic method are derived. Some properties of the hypernuclous Heare given as the illustrative example of the application of this method.

New insights into the role of PML in tumour suppression

The PML gene is involved in the t（15;17） translocation of acute promyelocytic leukaemia （APL）, which generates the oncogenic fusion protein PML （promyelocytic leukaemia protein）-retinoic acid receptor alpha. The PML protein localises to a subnuclear structure called the PML nuclear domain （PML-ND）, of which PML is the essential structural component. In APL, PML-NDs are disrupted, thus implicating these structures in the pathogenesis of this leukaemia. Unexpectedly, recent studies indicate that PML and the PML-ND play a tumour suppressive role in several different types of human neoplasms in addition to APL. Because of PML＇s extreme versatility and involvement in multiple cellular pathways, understanding the mechanisms underlying its function, and therefore role in tumour suppression, has been a challenging task. In this review, we attempt to critically appraise the more recent advances in this field and propose new avenues of investigation.

PML nuclear body biogenesis and oligomerization-driven leukemogenesis

PML nuclear bodies(NBs),which are increasingly recognized as the central hub of many cellular signaling events,are superassembled spherical complexes with diameters of 0.1–2mm.Recent studies reveal that RING tetramerization and B1-box polymerization are key factors to the overall PML NBs assembly.The productive RBCC oligomerization allows subsequent PML biogenesis steps,including the PML auto-sumoylation and partners recruitment via SUMO–SIM interactions.In promyelocytic leukemia,the oncoprotein PML/RARa(P/R)inhibits PML NBs assembly and leads to a full-fledged leukemogenesis.In this review,we review the recent progress in PML and acute promyelocytic leukemia fields,highlighting the protein oligomerization as an important direction of future targeted therapy.

The Arabidopsis CROWDED NUCLEI genes regulate seed germination by modulating degradation of ABI5 protein

In Arabidopsis, the phytohormone abscisic acid （ABA） plays a vital role in inhibiting seed germination and in postgermination seedling establishment. In the ABA signaling pathway, ABI5, a basic Leu zipper transcription factor, has important functions in the regulation of seed germination. ABI5 protein localizes in nuclear bodies, along with AFP, COP1, and SIZ1, and was degraded through the 26S proteasome pathway. However, the mechanisms of ABI5 nuclear body formation and ABI5 protein degradation remain obscure. In this study, we found that the Arabidopsis CROWDED NUCLEI （CRWN） proteins, predicted nuclear matrix proteins essential for maintenance of nuclear morphology, also participate in ABA-controlled seed germination by regulating the degradation of ABI5 protein. During seed germination, the crwn mutants are hypersensitive to ABA and have higher levels of ABI5 protein compared to wild type. Genetic analysis suggested that CRWNs act upstream of ABIS. The observation that CRWN3 colocalizes with ABI5 in nuclear bodies indicates that CRWNs might participate in ABI5 protein degrada- tion in nuclear bodies. Moreover, we revealed that the extreme C-terminal of CRWN3 protein is necessary for its function in the response to ABA in germination. Our results suggested important roles of CRWNs in ABI5 nuclear body organization and ABI5 protein degradation during seed germination.

Genome Organization and Function： A View from Yeast and Arabidopsis

Recent progress in understanding higher-order chromatin organization in the nucleus has been considerable. From single gene to chromosome territory, realistic biophysical models can now accurately predict some of the structural feature of cell nuclei. Despite growing evidence of a deterministic nuclear organization, the physiological consequence of spatial genome organization is still unclear. In the simple eukaryotic model, Saccharomyces cerevisiae, clear correlation between gene position and transcription has been established. In this review, we will focus on higher-order chromatin organization in yeast with respect to the nuclear envelope and nucleolus. In Arabidopsis thaliana, a model plant for which we have a complete genome sequence, chromosome territory （CT） arrangement and somatic homologous pairing in interphase nuclei seem to occur randomly. Since chromosomes containing nucleolar organizer regions associate more frequently to form a single nucleolar structure, as in yeast, the nucleolus seems to play a major role in organizing nuclear space. Recent findings have begun to elucidate how plant regulatory factors, such as chromatin remodeling or histone chaperones, affect the chromatin state of ribosomal DNA genes located in two distinct CTarrangements in the nucleus. The functional outcome of yeast nuclear organization allowed us to propose how nuclear organization might contribute to a novel type of epigenetic regulation： the spatial regulation of transcription.

Intracellular aggregations of biological elements:From simple to complex

Most cellular elements could be functioned by forming aggregate structures through interactions with other molecules,which is like the luminescence mechanism of AIE molecules.However,in comparison to AIE molecules,the aggregation of biological elements appears to be more complex due to membership and mechanism,which is in line with the trend in biological evolution following the principle of simplicity to complexity.Here,we chose three distinctive examples because they differ significantly in their composition and show a progression from simple to complex,namely protein–protein complexes,protein–nucleic acid complexes,and protein–nucleic acid–lipid complexes.The majority of units that perform functions within cells belong to these three types.We discuss the formation mechanisms and related functions of the protein–protein complex(PML-NB),the proteins–nucleic acids complex ribosome,and the proteins–nucleic acids–lipids complex exosome,and hope to provide expert insight for related fields.

ISWI ATP-dependent remodeling of nucleoplasmic u-speckles in the brain of Drosophila melanogaster

Heterogeneous nuclear ribonucleoproteins（hn RNPs） belong to the RNA-binding proteins family. They are involved in processing heterogeneous nuclear RNAs（hn RNAs） into mature m RNAs. These proteins participate in every step of m RNA cycle, such as m RNA export, localization, translation, stability and alternative splicing. At least 14 major hn RNPs, which have structural and functional homologues in mammals, are expressed in Drosophila melanogaster. Until now, six of these hn RNPs are known to be nucleus-localized and associated with the long non-coding RNA（lnc RNA） heat shock responsive u（hsru）in the omega speckle compartments（u-speckles）. The chromatin remodeler ISWI is the catalytic subunit of several ATP-dependent chromatin-remodeling complexes, and it is an essential factor for organization of u-speckles. Indeed, in ISWI null mutant, severe defects in u-speckles structure are detectable. Here, we clarify the role of ISWI in the hn RNPs-hsru interaction. Moreover, we describe how ISWI by its remodeling activity, controls hsru and hn RNPs engagement in u-speckles. Finally, we demonstrate that the sequestration of hn RNPs in u-speckles nuclear compartment is a fundamental event in gene expression control and represents a key step in the regulation of several pathways.