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      Volume 42, Issue 1

      March 2017,   pages  1-207

    • Evolution acting on the same target, but at multiple levels: Proteins as the test case

      Basuthkar J Rao

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    • Sherlock Holmes, David Perkins, and the missing Neurospora inversions

      DURGADAS P KASBEKAR

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    • What history tells us XLII. A ‘new’ view of proteins

      MICHEL MORANGE

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    • Neurospora tetrasperma crosses heterozygous for hybrid translocation strains produce rare eight-spored asci-bearing heterokaryotic ascospores

      DURGADAS P KASBEKAR SELVAM REKHA

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      During ascogenesis in Neurospora, the ascospores are partitioned at the eight-nucleus stage that follows meiosis and apost-meiotic mitosis, and the ascospores that form in eight-spored asci are usually homokaryotic. We had previouslycreated novel TNt strains by introgressing four Neurospora crassa insertional translocations (EB4, IBj5, UK14-1, andB362i) into N. tetrasperma. We now show that crosses of all the TNt strains with single-mating-type derivatives of thestandard N. tetrasperma pseudohomothallic strain 85 (viz. TNta × 85A or TNtA × 85a) can produce rare eight-sporedasci that contain heterokaryotic ascospores, or ascospores with other unexpected genotypes. Our results suggest thatthese rare asci result from the interposition of additional mitoses between the post-meiotic mitosis and the partitioningof nuclei into ascospores, leading to the formation of supernumerary nuclei that then generate the heterokaryoticascospores. The rare asci probably represent a background level of ascus dysgenesis wherein the partitioning ofascospores becomes uncoupled from the post-meiotic mitosis. Ordinarily, the severest effect of such dysgenesis, theproduction of mating-type heterokaryons, would be suppressed by the N. crassa tol (tolerant) gene, thus explainingwhy such dysgenesis remained undetected thus far.

    • Overexpression of hsa-miR-939 follows by NGFR down-regulation and apoptosis reduction

      FAHIMEH HOSSEINI AGHDAEI BAHRAM M SOLTANI SADAT DOKANEHIIFARD SEYED JAVAD MOWLA MASOUD SOLEIMANI

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      Neurotrophin receptors play a crucial role in neuronal survival, differentiation and regeneration. Nerve growthfactor receptor (NGFR) or P75NTR is a neurotrophin receptor that is involved in many pathological conditionsincluding cancers. Genetic factors that are involved in regulation of neurotrophin receptors are under intenseinvestigation. MiRNAs are novel regulators of signalling pathways that are candidates for regulation ofneurotrophin receptors. Computational programs predicted that NGFR gene is a bona fide target for hsa-miR-939. RT-qPCR, Western analysis and dual luciferase assay evidences indicated that NGFR transcript is targetedby hsa-miR-939. Also, hsa-miR-939 overexpression brought about down-regulation of NGFR expression in U87cell line, followed by cell death rate reduction, detected by flow cytometry. Taken together, here for the first time,hsa-miR-939 is introduced as a novel key regulator of NGFR expression and its involvement in cell death/survivalprocesses is suggested.

    • Constitutively activated ERK sensitizes cancer cells to doxorubicin: Involvement of p53-EGFR-ERK pathway

      RATNA KUMARI SURBHI CHOUHAN SNAHLATA SINGH RISHI RAJ CHHIPA AMRENDRA KUMAR AJAY MANOJ KUMAR BHAT

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      The tumour suppressor gene p53 is mutated in approximately 50% of the human cancers. p53 is involved in genotoxicstress-induced cellular responses. The role of EGFR and ERK in DNA-damage-induced apoptosis is well known. Weinvestigated the involvement of activation of ERK signalling as a consequence of non-functional p53, in sensitivity ofcells to doxorubicin. We performed cell survival assays in cancer cell lines with varying p53 status: MCF-7 (wild-typep53, WTp53), MDA MB-468 (mutant p53, MUTp53), H1299 (absence of p53, NULLp53) and an isogenic cell lineMCF-7As (WTp53 abrogated). Our results indicate that enhanced chemosensitivity of cells lacking wild-type p53function is because of elevated levels of EGFR which activates ERK. Additionally, we noted that independent of p53status, pERK contributes to doxorubicin-induced cell death.

    • CSFV proliferation is associated with GBF1 and Rab2

      WULONG LIANG MINPING ZHENG CHANGLEI BAO YANMING ZHANG

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      The Golgi apparatus and its resident proteins are utilized and regulated by viruses to facilitate their proliferation. Inthis study, we investigated Classical swine fever virus (CSFV) proliferation when the function of the Golgi wasdisturbed. Golgi function was disturbed using chemical inhibitors, namely, brefeldin A (BFA) and golgicide A (GCA),and RNA interfering targets, such as the Golgi-specific BFA-resistance guanine nucleotide exchange factor 1 (GBF1)and Rab2 GTPases. CSFV proliferation was significantly inhibited during RNA replication and viral particlegeneration after BFA and GCA treatment. CSFV multiplication dynamics were retarded in cells transfected withGBF1 and Rab2 shRNA. Furthermore, CSFV proliferation was promoted by GBF1 and Rab2 overexpression using alentiviral system. Hence, Golgi function is important for CSFV multiplication, and GBF1 and Rab2 participate inCSFV proliferation. Further studies must investigate Golgi-resident proteins to elucidate the mechanism underlyingCSFV replication.

    • AtMBD6, a methyl CpG binding domain protein, maintains gene silencing in Arabidopsis by interacting with RNA binding proteins

      ADWAITA PRASAD PARIDA AMRAPALI SHARMA ARUN KUMAR SHARMA

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      DNA methylation, mediated by double-stranded RNA, is a conserved epigenetic phenomenon that protects a genome fromtransposons, silences unwanted genes and has a paramount function in plant or animal development. Methyl CpG bindingdomain proteins are members of a class of proteins that bind tomethylated DNA. The Arabidopsis thaliana genome encodes13 methyl CpG binding domain (MBD) proteins, but themolecular/biological functions of most of these proteins are still notclear. In the present study, we identified four proteins that interact with AtMBD6. Interestingly, three of them contain RNAbinding domains and are co-localized with AtMBD6 in the nucleus. The interacting partners includes AtRPS2C (a 40Sribosomal protein), AtNTF2 (nuclear transport factor 2) and AtAGO4 (Argonoute 4). The fourth protein that physicallyinteracts with AtMBD6 is a histone-modifying enzyme, histone deacetylase 6 (AtHDA6), which is a known component ofthe RNA-mediated gene silencing system. Analysis of genomic DNA methylation in the atmbd6, atrps2c and atntf2mutants, using methylation-sensitive PCR detected decreased DNA methylation at miRNA/siRNA producing loci,pseudogenes and other targets of RNA-directed DNA methylation. Our results indicate that AtMBD6 is involved inRNA-mediated gene silencing and it binds to RNA binding proteins like AtRPS2C, AtAGO4 and AtNTF2. AtMBD6 alsointeracts with histone deacetylase AtHDA6 that might have a role in chromatin condensation at the targets of RdDM.

    • Extra-oviductal expression of oviductal glycoprotein 1 in mouse: Detection in testis, epididymis and ovary

      SANIYA LAHERI DEEPAK MODI PURVI BHATT

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      Oviductal glycoprotein 1 (OVGP1), also called oviductin, is an oviduct-specific protein and is suggested to play a rolein fertilization. Traditionally, Ovgp1 has been shown to be exclusively expressed by the oviduct; however, recentstudies have demonstrated its expression in some cancers. This observation led us to hypothesize that Ovgp1 mighthave some extra-oviductal expression. In the current study, we evaluated the mRNA and protein expression of Ovgp1in normal reproductive tissues of male and female mice. For the first time, we demonstrate that beyond the oviduct,Ovgp1 mRNA is expressed in the testis, epididymis and ovary, but not in the uterus, cervix, vagina, breast, seminalvesicles and prostate gland. In the testis, Ovgp1 mRNA was localized in the cells at the base of seminiferous tubules(most likely, Sertoli cells), while the protein was detected in the round and elongating spermatids. In the epididymis,Ovgp1 transcripts were localized in epididymal epithelium of the caput but not the corpus and cauda; OVGP1 proteinwas, however, not detected in any of the segments but was present in the epididymal sperm. In the ovary, Ovgp1transcripts and protein were detected in the surface epithelium, granulosa cells of the preantral and the antral folliclesand corpus luteum. In both, the ovary and oviduct, the expression of Ovgp1 was found to be higher at estrus stage thanat diestrus stage. To the best of our knowledge, this is the first study demonstrating the extra-oviductal expression ofOvgp1. Our data suggests that, beyond fertilization, Ovgp1 might have specific roles in gonadal physiology.

    • Genetic architecture of seed longevity in bread wheat (Triticum aestivum L.)

      MIAN ABDUR REHMAN ARIF MANUELA NAGEL ULRIKE LOHWASSER ANDREAS BÖRNER

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      The deterioration in the quality of ex situ conserved seed over time reflects a combination of both physical andchemical changes. Intraspecific variation for longevity is, at least in part, under genetic control. Here, the grain of 183bread wheat accessions maintained under low-temperature storage at the IPK-Gatersleben genebank over somedecades have been tested for their viability, along with that of fresh grain subjected to two standard artificial ageingprocedures. A phenotype–genotype association analysis, conducted to reveal the genetic basis of the observedvariation between accessions, implicated many regions of the genome, underling the genetic complexity of the trait.Some, but not all, of these regions were associated with variation for both natural and experimental ageing, implyingsome non-congruency obtains between these two forms of testing for longevity. The genes underlying longevityappear to be independent of known genes determining dormancy and pre-harvest sprouting.

    • Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status

      DAIANE TEIXEIRA DE OLIVEIRA ANDRÉ LUIZ VENTURA SÁVIO JOÃO PAULO DE CASTRO MARCONDES TATIANE MARTINS BARROS LUDMILA CORREIA BARBOSA DAISY MARIA FAVERO SALVADORI GLENDA NICIOLI DA SILVA

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      Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness forpreventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activityof silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used:RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates,genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 andmiR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutatedcells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survivalassay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 andmiR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion,despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR,AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role ofsilibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.

    • MicroRNA-144 inhibits hepatocellular carcinoma cell proliferation, invasion and migration by targeting ZFX

      HONGBIN BAO XINGUO LI HENGLI LI HONGLI XING BINGHUI XU XIANFENG ZHANG ZHAOMING LIU

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      MicroRNA 144 (miR-144), a small non-coding RNA, is frequently dysregulated in human several tumour progression,but its role and the underlying mechanisms in hepatocellular carcinoma (HCC) is poorly investigated. In thepresent study, the expression of miR-144 was firstly analysed in datasets derived from GSE21362 and TCGA, andthen detected in HCC tissues and cell lines by quantitative RT-PCR (qRT-PCR) analysis. MiR-144 was shown to besignificantly down-regulated in HCC tissues and cell lines. Subsequently, overexpression of miR-144 was transfectedinto HCC cell lines so as to investigate its biological function, including MTT, colony formation, and transwell assays.Gain of function assay revealed miR-144 remarkably inhibited cell proliferation, migration and invasion. In addition,bioinformatical analysis and luciferase reporter assay identified ZFX as a novel target of miR-144 in HCC cells, asconfirmed by qRT-PCR and Western blot. Furthermore, ZFX was found to be significantly up-regulated usingOncomine database analysis. Loss of function assay further indicated knockdown of ZFX had similar effects ofmiR-144-mediated HCC cell proliferation and invasion. Therefore, miR-144 has been demonstrated to act as a tumoursuppressor in HCC cell growth and motility by directly targeting ZFX, which implicates its potential applications inthe development of HCC treatment.

    • Molecular analysis of the human faecal archaea in a southern Indian population

      SANDYA B RANI RAMADASS BALAMURUGAN BALAKRISHNAN S RAMAKRISHNA

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      Archaea are an important constituent of the human gut microbiota, but there is no information on human gut archaea inan Indian population. In this study, faecal samples were obtained from different age groups (neonatal babies, preschoolchildren, school-going children, adolescents, adults and elderly) of a southern Indian population, and from atribal population also resident in southern India). 16S rRNA gene sequences specific to Archaea were amplified frompooled faecal DNA in each group, sequenced, and aligned against the NCBI database. Of the 806 adequate sequencesin the study, most aligned with 22 known sequences. There were 9 novel sequences in the present study. All sequenceswere deposited in the GenBank nucleotide sequence database with the following accession numbers: KF607113 -KF607918. Methanobrevibacter was the most prevalent genus among all the age groups accounting for 98% inneonates, 96% in post-weaning, and 100% each in preschool, school and adult population. In the elderly, Methanobrevibacteraccounted for 96% and in tribal adults, 99% of the clones belonged to Methanobrevibacter genus. Othergenera detected included Caldisphaera, Halobaculum, Methanosphaeraand Thermogymnomonas. Methanobrevibactersmithii predominated in all age groups, accounting for 749 (92.9%) of the 806 sequences. Archaea can befound in the faeces of southern Indian residents immediately after birth. Methanobrevibacter smithii was the dominantfaecal archeon in all age groups, with other genera being found at the extremes of age.

    • Breviscapine suppresses the growth of non-small cell lung cancer by enhancing microRNA-7 expression

      JIAN ZENG SHUNV CAI

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      Breviscapine (BVP) has previously been shown to inhibit the proliferation of hepatocellular carcinoma cells.However, little is known about the effects of BVP on non-small cell lung cancer (NSCLC) growth. Here, we aimedto study the effects of BVP on human NSCLC growth. We employed A549, NCL-H460 and A549 cells transfectedwith microRNA-7 (miR-7) mimic and inhibitor to investigate the effect of BVP on cell proliferation, apoptosis andapoptosis-associated molecules. The results showed that BVP significantly reduced the growth of A549 and NCLH460cells in a concentration-dependent and time-dependent manner, accompanied by a significant elevation ofapoptosis. Additionally, the present study also confirmed that BVP-treated A549 cells showed increased levels of Baxand microRNA-7 (miR-7) and a decreased level of Bcl-2. The up-regulation of miR-7 enhanced the BVP sensitivity ofNSCLC cells by suppressing cell proliferation and promoting cell apoptosis, while the inhibition of miR-7 reversedthe anti-proliferative pro-apoptotic effects of BVP. Pre-treatment with miR-7 mimics enhanced the BVP-mediateddown-regulation of Bax/Bcl-2 in NSCLC cells, while pre-treatment with the miR-7 inhibitor blocked the BVPmediateddown-regulation of Bax/Bcl. Taken together, these results confirm that BVP effectively inhibits NSCLCproliferation and that miR-7, as a novel target, is likely involved in BVP-induced growth suppression and theapoptosis of NSCLC cells.

    • Early life stress experience may blunt hypothalamic leptin signalling

      JH LEE SB YOO JY KIM JY LEE BT KIM K PARK JW JAHNG

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      The aim of this study was to investigate whether neonatal maternal separation (MS) – chronic stress experience inearly life – affects the anorectic efficacy of leptin in the offspring at adolescence. Sprague–Dawley pups wereseparated from the dam daily for 3 h during postnatal day 1–14 or left undisturbed as non-handled controls (NH).NH and MS male pups received an intraperitoneal leptin (100 μg/kg) or saline on postnatal day (PND) 28, and thenfood intake and body weight gain were recorded. The hypothalamic levels of leptin-signalling-related genes,phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and protein-tyrosine phosphatase 1B(PTP1B) were examined at 40 min after a single injection of leptin on PND 39 by immunohistochemistry and Westernblot analysis. Leptin-induced suppressions in food intake and weight gain was observed in NH pups, but not in MS.Leptin increased pSTAT3 in the hypothalamic arcuate nucleus of NH pups, but not of MS. Interestingly, basal levelsof the hypothalamic PTP1B and pSTAT3 were increased in MS pups compared with NH controls. The results suggestthat neonatal MS experience may blunt the anorectic efficacy of leptin later in life, possibly in relation with increasedexpressions of PTP1B and/or pSTAT3 in the hypothalamus.

    • Female conspecifics restore rhythmic singing behaviour in arrhythmic male zebra finches

      NEELU ANAND JHA VINOD KUMAR

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      The present study investigated whether pairing with a conspecific female would restore rhythmicity in the singingbehaviour of arrhythmic male songbirds. We recorded the singing and, as the circadian response indicator, monitoredthe activity–rest pattern in male zebra finches (Taeniopygia guttata) housed without or with a conspecific femaleunder 12 h light: 12 h darkness (12L:12D) or constant bright light (LLbright). Both unpaired and paired birds exhibiteda significant daily rhythm in the singing and activity behaviour, but paired birds, under 12L:12D, showed a ~2 hextension in the evening. Exposure to LLbright decayed rhythmicity, but the female presence restored rhythmic patternswithout affecting the 24 h song output. In the acoustic features, we found a significant difference in the motif durationbetween unpaired and paired male songs. Overall, these results demonstrated for the first time the role of the female inrestoring the circadian phenotype of singing behaviour in male songbirds with disrupted circadian functions, althoughhow interaction between sexes affects the circadian timing of male singing is not understood yet. It is suggested thatsocial cues rendered by a conspecific female could improve the circadian performance by restoring rhythmicity in thebiological functions of the cohabiting arrhythmic male partner.

    • Molecular mechanism of Endosulfan action in mammals

      ROBIN SEBASTIAN SATHEES C RAGHAVAN

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      Endosulfan is a broad-spectrum organochlorine pesticide, speculated to be detrimental to human health in areas ofactive exposure. However, the molecular insights to its mechanism of action remain poorly understood. In two recentstudies, our group investigated the physiological and molecular aspects of endosulfan action using in vitro, ex vivo andin vivo analyses. The results showed that apart from reducing fertility levels in male animals, Endosulfan inducedDNA damage that triggers compromised DNA damage response leading to undesirable processing of broken DNAends. In this review, pesticide use especially of Endosulfan in the Indian scenario is summarized and the importance ofour findings, especially the rationalized use of pesticides in the future, is emphasized.

    • Diverse roles of WDR5-RbBP5-ASH2L-DPY30 (WRAD) complex in the functions of the SET1 histone methyltransferase family

      AAMIR ALI SHWETA TYAGI

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      WD repeat containing protein 5 (WDR5), Retinoblastoma Binding Protein 5 (RbBP5), Absent-Small-Homeotic-2-Like protein (ASH2L), and Dumpy-30 (Dpy30) have been reported to be the integral and shared components of all theSET1 family of histone 3 lysine 4 histone methyltransferase (HMT) complexes. Collectively called the WRADcomplex, these proteins are pivotal to the HMT activity of the SET1 complexes. Recent reports highlight the novelnon-canonical functions of WRAD in cellular processes other than its well-studied role in histone methylation andgene expression. In this review, we examine the diversity in emerging transcription-independent functions of WRAD.

    • Immune modulation by dendritic-cell-based cancer vaccines

      CHAITANYA KUMAR SAKSHI KOHLI POONAMALLE PARTHASARATHY BAPSY ASHOK KUMAR VAID MINISH JAIN VENKATA SATHYA SURESH ATTILI BANDANA SHARAN

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      The interplay between host immunity and tumour cells has opened the possibility of targeting tumour cells bymodulation of the human immune system. Cancer immunotherapy involves the treatment of a tumour by utilizing therecombinant human immune system components to target the pro-tumour microenvironment or by revitalizing theimmune system with the ability to kill tumour cells by priming the immune cells with tumour antigens. In this review,current immunotherapy approaches to cancer with special focus on dendritic cell (DC)-based cancer vaccines arediscussed. Some of the DC-based vaccines under clinical trials for various cancer types are highlighted. Establishingtumour immunity involves a plethora of immune components and pathways; hence, combining chemotherapy,radiation therapy and various arms of immunotherapy, after analysing the benefits of individual therapeutic agents,might be beneficial to the patient.

    • Non-ribosomal peptide synthetases: Identifying the cryptic gene clusters and decoding the natural product

      MANGAL SINGH SANDEEP CHAUDHARY DIPTI SAREEN

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      Non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) present in bacteria and fungi are themajor multi-modular enzyme complexes which synthesize secondary metabolites like the pharmacologically importantantibiotics and siderophores. Each of the multiple modules of an NRPS activates a different amino or aryl acid,followed by their condensation to synthesize a linear or cyclic natural product. The studies on NRPS domains, theknowledge of their gene cluster architecture and tailoring enzymes have helped in the in silico genetic screening of theever-expanding sequenced microbial genomic data for the identification of novel NRPS/PKS clusters and thusdeciphering novel non-ribosomal peptides (NRPs). Adenylation domain is an integral part of the NRPSs and is thesubstrate selecting unit for the final assembled NRP. In some cases, it also requires a small protein, the MbtHhomolog, for its optimum activity. The presence of putative adenylation domain and MbtH homologs in a sequencedgenome can help identify the novel secondary metabolite producers. The role of the adenylation domain in the NRPSgene clusters and its characterization as a tool for the discovery of novel cryptic NRPS gene clusters are discussed.

    • Untranslated regions of mRNA and their role in regulation of gene expression in protozoan parasites

      SHILPA J RAO SANGEETA CHATTERJEE JAYANTA K PAL

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      Protozoan parasites are one of the oldest living entities in this world that throughout their existence have shown excellentresilience to the odds of survival and have adapted beautifully to ever changing rigors of the environment. In view of thedynamic environment encountered by them throughout their life cycle, and in establishing pathogenesis, it is unsurprisingthat modulation of gene expression plays a fundamental role in their survival. In higher eukaryotes, untranslated regions(UTRs) of transcripts are one of the crucial regulators of gene expression (influencing mRNA stability and translationefficiency). Parasitic protozoan genome studies have led to the characterization (in silico, in vitro and in vivo) of a largenumber of their genes. Comparison of higher eukaryotic UTRs with parasitic protozoan UTRs reveals the existence ofseveral similar and dissimilar facets of the UTRs. This review focuses on the elements of UTRs of medically importantprotozoan parasites and their regulatory role in gene expression. Such information may be useful to researchers in designinggene targeting strategies linked with perturbation of host-parasite relationships leading to control of specific parasites.

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