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Plan

Describe the types of non-coding RNAs now recognised and in the human genome and describe briefly what is known about their production and function. Plan. Introduction ‘Functional’ RNAs rRNA tRNA snRNA snoRNA Regulating RNAs siRNA miRNA piRNA Long ncRNAs Conclusion. Introduction.

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Plan

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  1. Describe the types of non-coding RNAs now recognised and in the human genome and describe briefly what is known about their production and function.

  2. Plan • Introduction • ‘Functional’ RNAs • rRNA • tRNA • snRNA • snoRNA • Regulating RNAs • siRNA • miRNA • piRNA • Long ncRNAs • Conclusion

  3. Introduction • Deviation from ‘central dogma’ of molecular biology • Importance of RNA as a catalyst, involvement in cellular defence and gene regulation • Division of essay: • ‘Functional’ RNAs – specific non-regulatory roles • Regulating RNAs – involved in regulation of transcription/translation, transposon movement, viral defence

  4. Functional RNAs • Ribosomal RNA (rRNA) key content: • Nuclear and mitochondrial subtypes • Nuclear: • Large/small subunits (60S/40S) • 40S: 18S RNA + protein • 60S: 5S, 5.8S, 28S + protein • 5.8, 18, 28S transcribed from single gene – 45S (5 transcribed separately) • 45S gene tandemly arrayed on short arms of acrocentric chromosomes 13,14,15,21,22 • 5S more dispersed, but do show some clustering • Function of rRNA (ribosome) is to translate mRNA • tRNA molecules sequentially added to growing polypeptide chain

  5. Functional RNAs ctd. • Transfer RNA (tRNA) • Structure of loops and ds segments formed by inverted repeats • Each tRNA has anti-codon and corresponding amino acid • Small (40S) rRNA subunit involved in tRNA codon/anti-codon recognition • Large (60S) rRNA subunit has catalytic action joining NH2 and CO2H groups in a condensation reaction • tRNA genes found in nuclear (hundreds) and mitochondrial (22) genomes • 49 tRNA subtypes; but 61 would be required to satisfy all coding triplets – wobble hypothesis

  6. Functional RNAs ctd • Small nuclear RNA (snRNA) • Catalytic RNA species involved in splicing • Major (GT-AG): U1, U2, (U4,5,6) • Minor (AT-AC): U11, U12, (U4,5,6) • Large number of proteins involved in spliceosome, but RNA is the vital unit • snRNA genes are found both dispersed and tandemly arrayed

  7. Functional RNAs ctd • Small nucleolar RNA (snoRNA) • Relatively small subgroup • Involved in specific modification of other nucleic acid species • Chiefly alter rRNA + snRNA: • Methylation (C/D box) • Pseudo-uridylation (uridine-pseudouridine) (H/ACA box) • Often found in the introns of other genes • SNURF/SNRPN – in PWAS region

  8. Regulation RNAs • Can be grouped into long and short RNAs • Short species have been well characterised, extent of long ncRNAs only recently realised

  9. Regulating RNAs ctd • siRNA • Mainly thought to be involved in defence against viral pathogens (but some endogenous siRNAs now recognised) • Initiating molecule is dsRNA approx. 70nt • Bound and processed to ~22nt by Dicer, then bound by Argonaut…ssRNA+AGO – RISC • RISC powerful inhibitor of complementary RNAs

  10. Regulating RNAs ctd • miRNA • Many miRNA genes now identified (e.g. lin4, let7) • Similarities with siRNA (size, Dicer/AGO) • But begin as long ssRNA transcript with inverted repeat (forms ‘lumpy’ dsRNA) • Active species binds to complementary mRNA 3’UTR to repress translation • Short ‘seed’ and <100% complementarity: • Single miRNA can target ‘battery’ of targets • Cell and tissue type specification? • Possibly miRNA production controlled by morphogens

  11. Regulating RNAs ctd • PIWI-interacting RNAs (piRNAs) • 25-30nt species • Mainly involved in transposon suppression • RNA+PIWI protein targets transposon RNA • Possible role in euchromatin remodelling

  12. Regulating RNAs ctd • Long non-coding RNAs (long ncRNAs) • Recognised for some time, but extent only recently being recognised: • Around 90% of genome is transcribed in at least 1D • But only 1-2% translated • ? How much of this is actually functional • Include 7SKRNA + Xist (+TSIX) • Functional mechanisms • Cleavage to shorter species • Structural • Trans-activating (Hox genes) • Epigenetic control • The amount of the ncRNA for organisms correlates with complexity - ?driving force for higher organism evolution

  13. References • Small silencing RNAs: an expanding universe • Nature reviews genetics, Feb 09 • Science Vol 319, March 08 – several papers • Non-coding RNA transcription: turning on neighbours • Nature cell biology, Vol 10, No.9, Sep 08

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