--- module: 091-02 language: en chapter: 91 title: "DNA Replication, Repair, Gene Expression, and Epigenetic Control" module_title: "Transcription, RNA processing, noncoding RNA, and post-transcriptional control" source_sha256: 1ef4d52cc5eb8284a183e7dc8f174193c475440fec1bdfe0ad50769d981d2487 --- # Transcription and RNA control ## RNA roles and polymerases ### RNA is catalyst, scaffold, guide, regulator ### Polymerase one: most ribosomal RNA ### Polymerase two: messenger and many noncoding RNAs ### Polymerase three: transfer, 5S, small RNAs ### Template read 3' to 5', RNA made 5' to 3' ## Initiation and elongation ### Activators, general factors, mediator assemble ### Not every promoter has a TATA box ### Carboxyl-terminal domain phosphorylation #### Escape into elongation #### Recruits RNA-processing factors ### Enhancers act at distance, either orientation #### Silencers and insulators constrain #### Noncoding variants alter quantity, timing, place ### Elongation meets nucleosomes and supercoiling ### Promoter-proximal pausing keeps genes poised ### Transcription rate shapes splicing choice ## Capping and splicing ### Seven-methylguanosine cap, 5'-5' bond #### Protects, recruits export, supports translation ### snRNPs recognise splice sites and branch point ### Two transesterifications form a lariat #### No direct ATP for bond chemistry ### Alternative splicing expands diversity #### Prominent in brain, muscle, development ### Splicing variants #### Synonymous change can be pathogenic #### Deep intronic variants create pseudoexons #### Relevant tissue RNA, blood may lack it ## Three-prime end, export, and localisation ### Cleavage and poly-A tail addition ### Alternative polyadenylation #### Changes microRNA sites, localisation, product ### Histone messenger RNAs non-polyadenylated ### Quality-checked export through nuclear pores #### Faulty transcripts degraded by nuclear exosome ### Local translation in dendrites and axons ## Decay and surveillance ### Deadenylation starts decay #### Decapping and exonuclease, or exosome ### AU-rich elements tune inflammatory transcripts ### Stability changes act faster than transcription ### Nonsense-mediated decay #### Loss through RNA degradation #### Escape gives dominant-negative products ### Nonstop, no-go, ribosome quality control #### Neurons especially vulnerable ## Editing and chemical modification ### Adenosine-to-inosine editing by ADAR #### Inosine read as guanosine ### Cytidine editing: apolipoprotein B48 ### Editing is not genomic mutation ### N6-methyladenosine writers and readers ### Epitranscriptome mapping needs careful controls ## Small regulatory RNAs ### MicroRNAs processed by Drosha and Dicer #### Seed pairing lowers translation or stability #### Many modest targets per microRNA ### Small interfering RNAs: extensive pairing, cleavage #### Delivery, off-target, immune limits #### Does not alter genomic DNA ## Long, circular, and structural RNAs ### Long noncoding RNAs over about 200 nucleotides #### XIST initiates dosage compensation #### Expression alone does not prove function ### Circular RNAs from back-splicing ### Small nucleolar RNAs guide rRNA modification ### Membraneless condensates #### Stress granules sequester translation parts #### Processing bodies hold decay factors ## Interpretation, measurement, and therapy ### One gene, many outputs #### Identify the tissue-relevant transcript ### Measurement methods carry biases #### RNA level is not protein level ### Antisense, interfering, messenger, guide RNA therapies #### Modification and delivery improve targeting ### Normal coding sequence is not normal expression