LS14Mutations - Lecture 14: Genetic mutation Multiple...

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1 Lecture 14: Genetic mutation Multiple levels of gene regulations Different types of mutations Effects of mutations to gene expression and functions What cause cancer? Regulation of gene expression at multiple levels
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2 1. Nuclear pore and nuclear transport Nuclear pore structure contains 50-100 proteins called nucleoporins. In the cell, molecules smaller than ~60kD can diffuse freely through the nuclear pores, but those larger than 60kD cannot diffuse and they need selective transportation in or out of the nucleus. NLS: N uclear L ocalization S ignal of nuclear proteins Large nuclear proteins contain NLS. There are many different NLS sequences, often rich in basic amino acids. The SV40 NLS sequence, PKKKRLV , was the first one characterized. The NLS of a nuclear protein (X) can be fused, using recombinant DNA method, to a cytoplasmic protein (Y) to force the recombinant Y move into the nucleus Native pyruvate kinase is a cytoplasmic protein The pyruvate kinase fused to SV40-NLS is now in the nucleus
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3 Nuclear import of proteins 1. Importin binds to NLS of the protein to be imported (cargo) 2. Importin-cargo complex move through nuclear pore with the help of a G-protein called RAN 3. When inside the nucleus, RAN exchanges its GDP to GTP, resulting in release of the cargo. 4. Importin-RAN-GTP moves out to the cytosol to be recycled Nuclear export of proteins 1. The protein to be exported from the nucleus usually contain nuclear export signal ( NES ). 2. Exportin-RAN-GTP complex binds to NES of the protein to be exported (cargo) 3. Exportin-RAN-GTP-cargo complex moves through nuclear pore out of the nuclear pore 4. When outside the nucleus, RAN exchanges its GTP to GDP, resulting in disintegration of exportin- RAN complex 5. Exportin moves back to the nucleus with RAN-GDP to be recycled
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4 Export of mRNA from the nucleus 1. mRNA binds to hnRNP proteins to form mRNP . 2. mRNP binds to a protein called mRNA-exporter 3. mRNA-exporter interacts with nuclear pore protein to move mRNP out of the nucleus 4. Many mRNA processing proteins are also involved in mRNA exportation, including some exon-junction-binding proteins , cap- binding proteins , and nuclear polyA-binding proteins 5. Pre-mRNA's associated with splicesome cannot be exported 2. miRNA, RNAi, and siRNA (1) Micro RNA (miRNA): micro RNA's are 21-22 nt long single strand RNA generated from a ~70nt long stem-loop miRNA precursors. Micro RNAs are encoded by micro RNA genes in animals and plants, their function is usually to suppress translation of other mRNA that have sequence homology with miRNA. The miRNA binds target mRNA by imperfect base-pairing. (2) RNA interference (RNAi):
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This note was uploaded on 01/16/2010 for the course LIFESCI Life scien taught by Professor Lorenz,t.c. during the Fall '09 term at UCLA.

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LS14Mutations - Lecture 14: Genetic mutation Multiple...

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