Day 2 :
- Track 1: Nucleic Acids
Location:
Session Introduction
Eylon Yavin
The Hebrew University of Jerusalem, Israel
Title: Peptide Nucleic Acids (PNAs) as antimalaria agents
Time : 10:30-11:00
Biography:
Eylon Yavin has completed his PhD at the Weizmann Institute of Science (Israel). He did his Post-doctoral work at the laboratory of Prof. Jacqueline Barton at Caltech (CA, USA). In 2006, he joined the School of Pharmacy at Jerusalem as a faculty member. He is currently a Senior Lecturer and has an active research lab in the field of Nucleic Acids. He has published more than 40 papers in reputed journals and has been recently elected as the President of The Medicinal Chemistry Section of the Israel Chemical Society.
Abstract:
Specific silencing of essential genes by antisense oligonucleotides (ASOs) has been proposed as an alternative approach that may result in antimalarial activity which is not associated with drug resistance. Here, we present the use of peptide nucleic acids (PNAs) as a useful tool for gene silencing in Plasmodium falciparum; the most lethal parasite in malaria. PNAs, designed as specific antisense molecules, were conjugated to a cell penetrating peptide (CPP) to allow facile internalization into Plasmodium falciparum infected red blood cells. PNAs simply added to cultures were found exclusively in infected erythrocytes. We show that these PNAs specifically down regulated both stably expressed transgene as well as an endogenous gene, which significantly reduced parasites viability. In addition, we show that PNA targeting an antisense lncRNA in Plasmodium falciparum affects the expression profile of Var genes; an approach that could lead to more effective clearance of the parasite by the human immune system
Thenmalarchelvi Rathinavelan
Indian Institute of Technology Hyderabad, India
Title: Give and take: ‘Z-philic’ A...A mismatch in a GAC repeat promotes interaction with Zα binding domain of human ADAR1 protein
Time : 11:00-11:30
Biography:
Rathinavelan has completed her PhD from Department of Crystallography and Biophysics, University of Madras. Subsequently, she did her postdoctoral studies from Center for Bioinformatics/Department of Molecular Biosciences, The University of Kansas, US. Currently, she is working as an Assistant Professor in IIT Hyderabad and she has published more than 10 research papers in reputed journals.
Abstract:
Tandem repeats or microsatellites are abundant in eukaryotic genomes and are polymorphic in nature. Abnormal expansion of such tandem repeats in different sequence contexts cause many incurable genetic diseases. These over expansions lead to genome instability irrespective of its location in the genome by forming unusual secondary structures comprising of non-canonical base pairs. By employing molecular dynamics simulation technique, here we investigate the structural traits of DNA d(GAC)6.d(GAC)6 hairpin containing A...A mismatch that is associated with pseudoachondroplasia and multiple epiphysial displasias. Results show local B-to-Z DNA formation akin to d(CAG)6.d(CAG)6 repeat. This finding is further corroborated by titrating d(GAC)5.d(GAC)5 with different concentrations of salt (NaCl) and Zα binding domain of human ADAR1 proteinusing circular dichroism studies. Comparison of canonical d(GAC)5.d(GTC)5 with non-canonical d(GAC)5.d(GAC)5 duplexes confirms that non-isosterisity of A...A mismatch impels Z-DNA formation in the latter, thereby, facilitating the binding with Zα binding domain of human ADAR1 protein. As this is the first study that shows the binding of A…A mismatch containing d(GAC)5.d(GAC)5 duplex with an Z-DNA binding protein, it opens up a new avenue to investigate the role of Z-DNA binding proteins in trinucleotide repeat expansion disorders. Further, even a single A...A mismatch that intervenes canonical base pairs in the following sequence contexts: 5’GAA-3’CAT, 5’GAG-3’CAC, 5’AAC-3’TAG, 5’AAG-3’TAC, 5’TAA-3’AAT, 5’TAT-3’AAA, 5’CAA-3’GAT and 5’AAT-3’TAA (A…A mismatch underlined) also forms B-Z junction at the mismatch site. Such B-Z transition imposed by non-canonical A...A mismatch irrespective of the flanking sequence may have an impact on binding with mismatch repair or regulatory proteins and the accompanying biological processes.
Pinar Tulay Vehit
Near East University, Cyprus
Title: Differential expression of parental alleles of BRCA1 in human preimplantation embryos
Biography:
Dr. Pinar Tulay was born in Nicosia, 8th October 1985. She completed her high school education in Turk Maarif Koleji in Nicosia Cyprus. She graduated from University of Missouri in 2006 with double degree in Chemistry and Mathematics (B.Sc.).In 2007, she joined the Chemical Biology Department at Imperial College for her Master’s in Research (MRes) degree in Biomedical Physical Chemistry. Her work focused on investigating the role of N-myristole enzyme in cancer. In 2009, she joined the University College London (UCL) Centre for Preimplantation Genetic Diagnosis (PGD) team.Dr. Tulay is a member of international societies of Preimplantation Genetic Diagnosis International Society (PGDIS) and European Society of Human Reproduction and Embryology (ESHRE).
Abstract:
Introduction: The expression of parental genomes is required for completion of embryogenesis. Differential methylation of each parental genome has been observed in mouse and human preimplantation embryos. It is possible that differences in methylation affect the level of gene transcripts from each parental genome in early developing embryos. The aim of this study was to investigate if there is a parent specific pattern of BRCA1 expression in human embryos and to examine if this affects embryo development when the embryo carries a BRCA mutation. Materials and Methods: Differential parental expression of ACTB, SNRPN, H19 and BRCA1 was semi-quantitatively analysed by mini-sequencing in 95 human preimplantation embryos obtained from couples undergoing preimplantation genetic diagnosis (PGD). Results: BRCA1 was shown to be differentially expressed favouring the paternal transcript in early developing embryos. Methylation specific PCR showed a variable methylation profile of BRCA1 promoter region at different stages of embryonic development. Embryos carrying paternally inherited BRCA mutations were shown to develop more slowly compared to the embryos with maternally inherited BRCA mutations. Conclusions: The results of this study suggest that differential gene expression can influence the early development of preimplantation embryos. When the paternal BRCA1 transcript present in the embryo carries a mutation, the embryo may become more vulnerable to stress due to rapid demethylation of the paternal genome and the gradual demethylation of the maternal genome. Further extrapolation of this data suggests that the risk of transmitting a BRCA mutation may be modulated by the parental origin of the mutation.