Anticancer drugs resistance is a complex process that arises from altering in the drug targets. Advances in the DNA microarray, proteomics technology and the development of targeted therapies provide the new strategies to overcome the drug resistance. Although a design of the new chemotherapy agents is growing quickly, effective chemotherapy agent has not been discovered against the advanced stage of cancer (such as invasion and metastasis). The cancer cell resistance against the anticancer agents can be due to many factors such as the individual's genetic differences, especially in tumoral somatic cells. Also, the cancer drug resistance is acquired, the drug resistance can be occurred by different mechanisms, including multi-drug resistance, cell death inhibiting (apoptosis suppression), altering in the drug metabolism, epigenetic and drug targets, enhancing DNA repair and gene amplification. In this review, we outlined the mechanisms of cancer drug resistance and in following, the treatment failures by common chemotherapy agents in the different type of cancers.

https://apb.tbzmed.ac.ir/PDF/APB_386_20170226104729

The Different Mechanisms of Cancer Drug Resistance: A Brief Review.

The regulation of gene expression is mediated by interactions between chromatin and protein complexes. The importance of where and when these interactions take place in the nucleus is currently a subject of intense investigation. Increasing evidence indicates that gene activation or silencing is often associated with repositioning of the locus relative to nuclear compartments and other genomic loci. At the same time, however, structural constraints impose limits on chromatin mobility. Understanding how the dynamic nature of the positioning of genetic material in the nuclear space and the higher-order architecture of the nucleus are integrated is therefore essential to our overall understanding of gene regulation.

Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions

Chromosome territories--a functional nuclear landscape.

Increasing evidence suggests functional compartmentalization of interphase nuclei. This includes preferential interior localization of gene-rich and early replicating chromosome regions versus peripheral localization of gene-poor and late replicating chromosome regions , association of some active genes with nuclear speckles or transcription "factories", and association of transcriptionally repressed genes with heterochromatic regions. Dynamic changes in chromosome compartmentalization imply mechanisms for long-range interphase chromatin movements. However, live cell imaging in mammalian cells has revealed limited chromatin mobility, described as "constrained diffusion". None of these studies, though, have examined a chromosome locus undergoing an inducible repositioning between two different nuclear compartments. Here we demonstrate migration of an interphase chromosome site from the nuclear periphery to the interior 1-2 hr after targeting a transcriptional activator to this site. Spot redistribution is perturbed by specific actin or nuclear myosin I mutants. Extended periods of chromosome immobility are interspersed with several minute periods in which chromosomes move unidirectionally along curvilinear paths oriented roughly perpendicular to the nuclear envelope at velocities of 0.1-0.9 microm/min over distances of 1-5 microm. Our results suggest an active mechanism for fast and directed long-range interphase chromosome movements dependent directly or indirectly on actin/myosin.

Long-Range Directional Movement of an Interphase Chromosome Site Dependent on Actin and Nuclear Myosin

This review is a short update on the diversity of swine biomedical models and the importance of genomics in their continued development. The swine has been used as a major mammalian model for human studies because of the similarity in size and physiology, and in organ development and disease progression. The pig model allows for deliberately timed studies, imaging of internal vessels and organs using standard human technologies, and collection of repeated peripheral samples and, at kill, detailed mucosal tissues. The ability to use pigs from the same litter, or cloned or transgenic pigs, facilitates comparative analyses and genetic mapping. The availability of numerous well defined cell lines, representing a broad range of tissues, further facilitates testing of gene expression, drug susceptibility, etc. Thus the pig is an excellent biomedical model for humans. For genomic applications it is an asset that the pig genome has high sequence and chromosome structure homology with humans. With the swine genome sequence now well advanced there are improving genetic and proteomic tools for these comparative analyses. The review will discuss some of the genomic approaches used to probe these models. The review will highlight genomic studies of melanoma and of infectious disease resistance, discussing issues to consider in designing such studies. It will end with a short discussion of the potential for genomic approaches to develop new alternatives for control of the most economically important disease of pigs, porcine reproductive and respiratory syndrome (PRRS), and the potential for applying knowledge gained with this virus for human viral infectious disease studies.

/pdf/advances-in-swine-biomedical-model-genomics-4pyos8240b.pdf

Advances in swine biomedical model genomics.

Genomes are housed within cell nuclei as individual chromosome territories. Nuclei contain several architectural structures that interact and influence the genome. In this review, we discuss how the genome may be organised within its nuclear environment with the position of chromosomes inside nuclei being either influenced by gene density or by chromosomes size. We compare interphase genome organisation in diverse species and reveal similarities and differences between evolutionary divergent organisms. Genome organisation is also discussed with relevance to regulation of gene expression, development and differentiation and asks whether large movements of whole chromosomes are really observed during differentiation. Literature and data describing alterations to genome organisation in disease are also discussed. Further, the nuclear structures that are involved in genome function are described, with reference to what happens to the genome when these structures contain protein from mutant genes as in the laminopathies.

The genome and the nucleus: a marriage made by evolution. Genome organisation and nuclear architecture.

Chromosomes are highly organized and compartmentalized in cell nuclei. The analysis of their position is a powerful way to monitor genome organization in different cell types and states. Evidence suggests that the organization of the genome could be functionally important for influencing different cellular and developmental processes, particularly at early stages of development (i.e. fertilization and the consequent entry of the sperm nucleus into the egg). The position of chromosomes in the sperm nucleus might be crucial, because their location could determine the time at which particular chromatin domains are decondensed and remodelled, allowing some epigenetic level of control or influence over subsequent paternal gene expression in the embryo. Here, we analyse genome organization by chromosome position in mammalian sperm nuclei from three breeds of pig, as a model species. We have mapped the preferential position of all chromosomes (bar one) in sperm nuclei in two dimensions and have established that the sex chromosomes are the most internally localized chromosomes in mature sperm. The distribution of two autosomes and chromosomes X and Y in sperm heads was compared in primary and secondary spermatocytes and spermatids in porcine testes. The sex chromosomes were found at the nuclear edge in primary spermatocytes, which correlates with the known position of the XY body and their position in somatic cells, whereas, in spermatids, the sex chromosomes were much more centrally located, mirroring the position of these chromosomes in ejaculated spermatozoa. This study reveals the temporal repositioning of chromosome territories in spermatogenesis.

/pdf/non-random-chromosome-positioning-in-mammalian-sperm-nuclei-40du3tsyxx.pdf

Non-random chromosome positioning in mammalian sperm nuclei, with migration of the sex chromosomes during late spermatogenesis.

Alterations in the nuclear positioning of chromosomes and specific genes during differentiation and development have suggested strongly the existence of a relationship between non-random organization of the genome and its function. In this study, we have examined the genome organization in interphase nuclei during adipogenesis, using the pig as a model organism. We hypothesized that changes in the gene expression profile and chromatin remodeling which occur during cellular differentiation would elicit repositioning of whole chromosomes, moving specific genes on them to different regions of the nucleus. We established an in vitro adipogenesis differentiation system using mesenchymal stem cells, derived from porcine bone marrow. The nuclear position of seven adipogenesis genes (PPARG, SREBF1, FABP4, CEBPA, CEBPB, CREB, and GATA2), two control genes (SOX9 and MYL1), and six chromosomes carrying these gene loci (SSC4, SSC6, SSC12, SSC13, SSC15, and SSC17) was determined. We found that during adipogenesis, using the in vitro stem cell model system, in contrast to our original hypothesis, the nuclear position of genes involved in adipogenesis was altered radically with the up-regulation of gene expression correlating with these genes becoming more internally located within nuclei. Chromosome territories, containing these genes, were also found to alter their nuclear position during the in vitro adipogenesis model, with the most dramatic repositioning being SSC4 that moved from the nuclear periphery towards the nuclear interior. We found that during in vitro adipogenesis chromosome territories decondensed and the genes were found on loops and projections of chromatin, away from the main body of the chromosomes. From our data, it appears that the temporal repositioning of genes, emanating away from chromosomes, during adipogenesis is correlated with gene activity, supporting models of the involvement of spatial genome repositioning in regulating gene expression and the nuclear interior being an important region of the nucleus for transcription.

The spatial repositioning of adipogenesis genes is correlated with their expression status in a porcine mesenchymal stem cell adipogenesis model system

Chromosome replication is regulated in all organisms at the assembly stage of the replication machinery at specific origins. In Escherichia coli, the DnaA initiator protein regulates the assembly of replication forks at oriC. This regulation can be undermined by defects in nucleic acid metabolism. In cells lacking RNase HI, replication initiates independently of DnaA and oriC , presumably at persisting R-loops. A similar mechanism was assumed for origin-independent synthesis in cells lacking RecG. However, recently we suggested that this synthesis initiates at intermediates resulting from replication fork fusions. Here we present data suggesting that in cells lacking RecG or RNase HI, origin-independent synthesis arises by different mechanisms, indicative of these two proteins having different roles in vivo . Our data support the idea that RNase HI processes R-loops, while RecG is required to process replication fork fusion intermediates. However, regardless of how origin-independent synthesis is initiated, a fraction of forks will proceed in an orientation opposite to normal. We show that the resulting head-on encounters with transcription threaten cell viability, especially if taking place in highly transcribed areas. Thus, despite their different functions, RecG and RNase HI are both important factors for maintaining replication control and orientation. Their absence causes severe replication problems, highlighting the advantages of the normal chromosome arrangement, which exploits a single origin to control the number of forks and their orientation relative to transcription, and a defined termination area to contain fork fusions. Any changes to this arrangement endanger cell cycle control, chromosome dynamics, and, ultimately, cell viability. IMPORTANCE Cell division requires unwinding of millions of DNA base pairs to generate the template for RNA transcripts as well as chromosome replication. As both processes use the same template, frequent clashes are unavoidable. To minimize the impact of these clashes, transcription and replication in bacteria follow the same directionality, thereby avoiding head-on collisions. This codirectionality is maintained by a strict regulation of where replication is started. We have used Escherichia coli as a model to investigate cells in which the defined location of replication initiation is compromised. In cells lacking either RNase HI or RecG, replication initiates away from the defined replication origin, and we discuss the different mechanisms by which this synthesis arises. In addition, the resulting forks proceed in a direction opposite to normal, thereby inducing head-on collisions between transcription and replication, and we show that the resulting consequences are severe enough to threaten the viability of cells.

/pdf/the-consequences-of-replicating-in-the-wrong-orientation-492dfqou06.pdf

The Consequences of Replicating in the Wrong Orientation: Bacterial Chromosome Duplication without an Active Replication Origin

Background/Aim: A limitation to successful cancer chemotherapy treatments is the acquisition of drug resistance. In advanced-stage ovarian cancer, the mammalian target of rapamycin (mTOR) pathway is up-regulated, and inhibition of this pathway increases chemosensitivity in ovarian carcinoma cell lines. In this study, the expression of DEPTOR, mTOR, RICTOR, RAPTOR and S6 kinases were investigated in SKOV-3 and PEO1 parental and the paclitaxel-resistant (TaxR) SKOV-3TaxR and PEO1TaxR cell lines. Materials and Methods: RT-PCR, immunofluorescent analysis and Western blotting were carried out. Results: Quantitative RT-PCR revealed significant up-regulation of DEPTOR in both paclitaxel-resistant cell lines. SKOV-3TaxR exhibited down-regulation of RICTOR, RAPTOR and mTOR, whereas PEO1-TaxR showed down-regulation of RAPTOR and up-regulation of RICTOR and mTOR. Semi-quantitative RT-PCR analysis revealed marked changes in the expression of p70S6K splice variants mRNA in PEO1TaxR. Moreover, the phosphorylation status of p70S6K at Ser371 appears to be cell-type specific. Conclusion: We hypothesize that mTOR signalling may play a role in mediating paclitaxel resistance in ovarian cancer.

/pdf/differential-expression-of-mtor-signalling-components-in-3aqppjusly.pdf

Helen A. Foster

Papers

The genome and the nucleus: a marriage made by evolution. Genome organisation and nuclear architecture.

Non-random chromosome positioning in mammalian sperm nuclei, with migration of the sex chromosomes during late spermatogenesis.

The spatial repositioning of adipogenesis genes is correlated with their expression status in a porcine mesenchymal stem cell adipogenesis model system

The Consequences of Replicating in the Wrong Orientation: Bacterial Chromosome Duplication without an Active Replication Origin

Differential expression of mTOR signalling components in drug resistance in ovarian cancer.