Current Genomics (v.14, #7)

Watching Every Step of the Way: Junin Virus Attenuation Markers in the Vaccine Lineage by Betina Inés Stephan, Mario Enrique Lozano, Sandra Elizabeth Goñi (415-424).
The Arenaviridae family includes several hemorrhagic fever viruses which are important emerging pathogens.Junin virus, a member of this family, is the etiological agent of Argentine Hemorrhagic Fever (AHF). A collaboration betweenthe Governments of Argentina and the USA rendered the attenuated Junin virus vaccine strain Candid#1. Arenavirusesare enveloped viruses with genomes consisting of two single-stranded RNA species (L and S), each carrying twocoding regions separated by a stably structured, non-coding intergenic region. Molecular characterization of the vaccinestrain and of its more virulent ancestors, XJ13 (prototype) and XJ#44, allows a systematic approach for the discovery ofkey elements in virulence attenuation. We show comparisons of sequence information for the S RNA of the strains XJ13,XJ#44 and Candid#1 of Junin virus, along with other strains from the vaccine lineage and a set of Junin virus field strainscollected at the AHF endemic area. Comparisons of nucleotide and amino acid sequences revealed different point mutationswhich might be linked to the attenuated phenotype. The majority of changes are consistent with a progressive attenuationof virulence between XJ13, XJ#44 and Candid#1. We propose that changes found in genomic regions with lownatural variation frequencies are more likely to be associated with the virulence attenuation process. We partially sequencedfield strains to analyze the genomic variability naturally occurring for Junin virus. This information, togetherwith the sequence analysis of strains with intermediate virulence, will serve as a starting point to study the molecularbases for viral attenuation.

NBN Gene Polymorphisms and Cancer Susceptibility: A Systemic Review by Francesco Berardinelli, Alessandra di Masi, Antonio Antoccia (425-440).
The relationship between DNA repair failure and cancer is well established as in the case of rare, high penetrantgenes in high cancer risk families. Beside this, in the last two decades, several studies have investigated a possible associationbetween low penetrant polymorphic variants in genes devoted to DNA repair pathways and risk for developingcancer. This relationship would be also supported by the observation that DNA repair processes may be modulated by sequencevariants in DNA repair genes, leading to susceptibility to environmental carcinogens. In this framework, the aimof this review is to provide the reader with the state of the art on the association between common genetic variants andcancer risk, limiting the attention to single nucleotide polymorphisms (SNPs) of the NBN gene and providing the variousodd ratios (ORs). In this respect, the NBN protein, together with MRE11 and RAD50, is part of the MRN complex whichis a central player in the very early steps of sensing and processing of DNA double-strand breaks (DSBs), in telomeremaintenance, in cell cycle control, and in genomic integrity in general. So far, many papers were devoted to ascertain possibleassociation between common synonymous and non-synonymous NBN gene polymorphisms and increased cancerrisk. However, the results still remain inconsistent and inconclusive also in meta-analysis studies for the most investigatedE185Q NBN miscoding variant.

Non-coding microRNAs are involved in multiple regulatory mechanisms underlying response of cancer cells tostress leading to apoptosis, cell cycle arrest and autophagy. Many molecular layers are implicated in such cellular responseincluding epigenetic regulation of transcription, RNA processing, metabolism, signaling. The molecular interrelationshipbetween tumor protein (TP)-p53 family members and specific microRNAs is a key functional network supportingtumor cell response to chemotherapy and potentially playing a decisive role in chemoresistance of human epithelial cancers.TP63 was shown to modulate the expression of numerous microRNAs involved in regulation of epithelial cell proliferation,differentiation, senescence, “stemness” and skin maintenance, epithelial/ mesenchymal transition, and tumorigenesisin several types of epithelial cancers (e.g. squamous cell carcinoma, ovarian carcinoma, prostate carcinoma, gastriccancer, bladder cancer, and breast tumors), as well as in chemoresistance of cancer cells. TP63/microRNA networkwas shown to be involved in cell cycle arrest, apoptosis, autophagy, metabolism and epigenetic transcriptional regulation,thereby providing the groundwork for novel chemotherapeutic venues.

Genetics of the First Seven Proprotein Convertase Enzymes in Health and Disease by Hannu Turpeinen, Zsuzsanna Ortutay, Marko Pesu (453-467).
Members of the substilisin/kexin like proprotein convertase (PCSK) protease family cleave and convert immaturepro-proteins into their biologically active forms. By cleaving for example prohormones, cytokines and cell membraneproteins, PCSKs participate in maintaining the homeostasis in a healthy human body. Conversely, erratic enzymatic functionis thought to contribute to the pathogenesis of a wide variety of diseases, including obesity and hypercholestrolemia.The first characterized seven PCSK enzymes (PCSK1-2, FURIN, PCSK4-7) process their substrates at a motif made up ofpaired basic amino acid residues. This feature results in a variable degree of biochemical redundancy in vitro, and consequently,shared substrate molecules between the different PCSK enzymes. This redundancy has confounded our understandingof the specific biological functions of PCSKs. The physiological roles of these enzymes have been best illustratedby the phenotypes of genetically engineered mice and patients that carry mutations in the PCSK genes. Recent developmentsin genome-wide methodology have generated a large amount of novel information on the genetics of the firstseven proprotein convertases. In this review we summarize the reported genetic alterations and their associated phenotypes.

Cisgenics - A Sustainable Approach for Crop Improvement by R. S. Telem, Shabir. H. Wani, N. B. Singh, R. Nandini, R. Sadhukhan, S. Bhattacharya, N. Mandal (468-476).
The implication of molecular biology in crop improvement is now more than three decades old. Not surprisingly,technology has moved on, and there are a number of new techniques that may or may not come under the geneticallymodified (GM) banner and, therefore, GM regulations. In cisgenic technology, cisgenes from crossable plants areused and it is a single procedure of gene introduction whereby the problem of linkage drag of other genes is overcome.The gene used in cisgenic approach is similar compared with classical breeding and cisgenic plant should be treatedequally as classically bred plant and differently from transgenic plants. Therefore, it offers a sturdy reference to treat cisgenicplants similarly as classically bred plants, by exemption of cisgenesis from the current GMO legislations. This reviewcovers the implications of cisgenesis towards the sustainable development in the genetic improvement of crops andconsiders the prospects for the technology.

Actin-associated Proteins in the Pathogenesis of Podocyte Injury by Fang-Fang He, Shan Chen, Hua Su, Xian-Fang Meng, Chun Zhang (477-484).
Podocytes have a complex cellular architecture with interdigitating processes maintained by a precise organizationof actin filaments. The actin-based foot processes of podocytes and the interposed slit diaphragm form the final barrierto proteinuria. The function of podocytes is largely based on the maintenance of the normal foot process structurewith actin cytoskeleton. Cytoskeletal dynamics play important roles during normal podocyte development, in maintenanceof the healthy glomerular filtration barrier, and in the pathogenesis of glomerular diseases. In this review, we focused onrecent findings on the mechanisms of organization and reorganization of these actin-related molecules in the pathogenesisof podocyte injury and potential therapeutics targeting the regulation of actin cytoskeleton in podocytopathies.