Biol115 The Thread of Life"

Transcription

1 Biol115 The Thread of Life" Lecture 9" Gene expression and the Central Dogma"... once (sequential) information has passed into protein it cannot get out again. " ~Francis Crick, 1958!

2 Principles of Biology & other references" Chapter Gene Expression (What is the central dogma)" Chapter Non-coding RNA (Overview only)" Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227, " 2"

3 Objectives" Explain the flow of biological information between the key molecules involved in transcription and translation." Examine criticisms and evidence against the Central Dogma." Key terms: central dogma, transcription, translation, reverse transcription, RNA viruses, prions, RNA editing, non-coding RNA" 3"

4 Development of the Central Dogma" Crick proposed the Central Dogma to indicate the direction of information flow: from nucleic acid to proteins." All possible directions of information flow" By 1958, some arrows were removed" 4"

5 The Central Dogma of Biology" The Central Dogma specifies that biological information stored in DNA is used to synthesise proteins via an RNA intermediate." The information flow is largely unidirectional, from DNA to protein." The information in DNA is also replicated before cell division." 5"

6 Genetic information is used to synthesise proteins" Genetic information refers to the linear sequence of nucleotides in DNA." The linear sequence of nucleotides in DNA specifies a linear sequence of amino acids " Linear sequence of amino acids = polypeptide or protein! 6"

7 RNA as viral genetic material " The broadest variety of RNA genomes is found in viruses that infect animals" Retroviruses use reverse transcriptase to copy their RNA genome into DNA" HIV (human immunodeficiency virus) is the retrovirus that causes AIDS (acquired immunodeficiency syndrome)! 7"

8 RNA as viral genetic material" The viral DNA that is integrated into the host genome is called a provirus! Unlike a prophage, a provirus remains a permanent resident of the host cell" The host s RNA polymerase transcribes the proviral DNA into RNA molecules" The RNA molecules function both as mrna for synthesis of viral proteins and as genomes for new virus particles released from the cell" 8"

9 Insert Fig P391" 9"

10 Insert Fig P390" 10"

11 Prions: the simplest infectious agents" Prions are slow-acting, virtually indestructible infectious proteins that cause brain diseases in mammals" Prions propagate by converting normal proteins into the prion version" Scrapie in sheep, mad cow disease, and Creutzfeldt-Jakob disease in humans are all caused by prions" 11"

12 Prions and Mad Cow disease" Section of " a brain from" a patient suffering from Creutzfeldt-Jakob disease (CJD) or spongiform encephalopathy (SE)" 12"

13 What are prions?" related to normal proteins of unknown " function" " Two versions of these proteins:" normal = PrP" abnormal = PrP * " " PrP" " 3-D models of normal PrP protein and abnormal, infectious PrP * " PrP * " 13"

14 Why did prions challenge the Central Dogma?" prion = infectious protein that appeared to replicate itself" Central Dogma = only DNA can produce new protein" Resolution of conflict:" New prions are formed by structural change of host prion-like proteins, not by synthesis of new protein." 14"

15 Lesson learned from prion infections: the Central Dogma is still valid" The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. (F.H.C. Crick, 1970)! 15"

16 RNA editing" 5 November 2010 Nature doi: /news " 19 May 2011 Nature doi: /news " " RNA editing is the site-specific modification of an RNA sequence from that of its template by mechanisms other than splicing." " Results in changes to the sequences of mrna such that the message no longer reflects the genetic code in DNA." " THR SER SER HIS" ACG UCG AGA CAU(mRNA)" " ACG UCG UGA CAU (mrna)" THR SER * " " HIS" Original Sequence" Edited Sequence" 16"

17 Editing of Glutamate receptor mrna in human neurons" Unlike RNA splicing, RNA editing changes the code in mrna (without changing the code in DNA)" Editing produces glutamate receptor proteins with varying receptor functions" Nishikura Nature Reviews Molecular Cell Biology 7, (December 2006) doi: / nrm2061" 17"

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19 Non-coding RNAs & heterochromatin formation" Non-coding RNA can silence genes i.e. inhibit gene expression" Non-coding RNA (e.g. sirna) can convert euchromatin into non-expressed heterochromatin." The non-coding RNA Xist (red) coats one of the two X chromosomes in females, compacting it into heterochromatin and inactivating it." 19"

20 Challenge to the Central Dogma" While RNA editing and non-coding RNA can alter the expression of genes, these phenomena do not invalidate the central dogma." once information has passed into protein it cannot get out again.! 20"

21 You should now be able to:" 1. Describe information flow in biological systems using the Central Dogma of molecular biology " 2. Explain how RNA viruses, prions, RNA editing and non-coding RNA may be used as examples to contradict the Central Dogma (although they do not)." 3. Describe how RNA editing provides a powerful mechanism to produce biological variation that is not of genetic origin." 4. Explain why mechanisms such as RNA editing and non-coding RNA-mediated gene silencing produce phenotypic variation, but that those variations are not genetic (heritable)." 21"