Sub-nuclear bodies Flashcards
What are sub-nuclear structures?
Discrete localisations within the nucleus
What is the nucleolus?
- composed of proteins & nucleic acids
- FC, DFC, GC
- ribosome biogenesis
How is the nucleolus formed?
- formed around NORs (tandem repeats of rRNA genes)
What are the roles of the 3 compartments of the nucleolus?
- FC - depot of rDNA genes
- DFC - Maturation of pre-mRNA transcripts
- GC - assembly of pre-ribosomal particles
What happens during ribosome biogenesis? (not in detail)
- rRNA genes, RNA pol I or II
- long precursor 45S pre-rRNA
- processing to 18S RNA, 5.8S, 5S & 28S RNA molecules
- guide RNAs, snoRNAs, snoRNPs
- maturation 40S and 60S
- exported through NPC
What are ribosomopathies?
A range of disorders in which genetic abnormalities cause impaired ribosome biogenesis/function
Examples of ribosomopathies?
- Diamond-Blackfan anemia
- Dyskeratosis congenita
- Treacher Collins syndrome (TCS)
Why is the nucelolus NOT a steady state structure?
3 types of nucleolar protein
- mainly in nucleus (fibrillarin)
- part time in nucelolus (ribosomal proteins)
- Time/condition dependent
How is the nucleolus associated with disease?
morphological changes involving
- change in ribosome biogenesis
- loss of proteins to the nucleolus
How can nucleoli be used to detect cancer?
- enlarged, prominent
- high growth rate
- can use a stain and use it as a BIOMARKER
what are the 2 links between ribosome and cancer?
- increased ribosome biogenesis
- deficiencies in ribosome function
Why do viruses redistribute proteins in or out of the nucleolus?
- utilise nucleolar proteins to enhance virus replication
- subvert anti-viral pathways
Why does coronavirus, which replicates in cytoplasm, encode protein localising to the nucleolus?
- sequester nucleolar proteins to enhance translation of viral mRNAs in the cytoplasm
What are the reasons for Herpes targeting the nucleolus?
- encodes 8 proteins which localise to nucleolus
- viral proteins localise at different stages
- Dramatic change of nucleolar proteome e.g. RNA processing, DNA synthesis, replication & repair
What sub-nuclear structures have splicing related functions?
- Nuclear speckles
- Cajal bodies
- Gems
What sub-nuclear structure has transcriptional repression?
- PcG Bodies
What sub-nuclear structure has protein complex assembly/modification?
- PML Bodies
What does the spliceosome consist of?
U1, U2, U4, U5, U6 snRNPs
approx. 125 proteins
What do cajal bodies (3-5 per cell) contain?
proteins that participate in biogenesis of mRNA
involved in maturation & assembly of snRNPs
What do nuclear gems contain?
- do NOT contain snRNPs
- contain SMN protein
- assist CBs in snRNP biogenesis
What is Spinal Muscular Atrophy?
- defect in SMN1 gene (essential for snRNP assembly)
- death of neuronal cells spinal cord
- muscle atrophy
What are nuclear speckles?
- enriched in pre-mRNA splicing factors
- irregular
- dynamic, components can cycle
What is the function of nuclear speckles?
- storage and modification for pre-mRNA splicing factors, including snRNPs
- CLOSE to ACTIVE GENES - enhance metabolic activity in mRNA maturation & export
- euchromatin
What is retinitis pigmentosa?
- mutation in splicing factor
- night blindness > tunnel > blind
- linked to splicing factor PRP31
What are Polycomb bodies?
CONTRAST to speckles
- gene repression
- associated with heterochromatin
- induce epigenetic silencing
- recruit complex, modify chromatin
- overexpression - cancer
What are PML bodies?
- promiscuous, diverse function
- favour sequesteration/release of proteins, post-trans mods
- respond to cellular stress
How do PML bodies form?
- dimerize, multimerize
- sumoylation - spherical
- SIM-containing, sumoylaed partners - recruited by SUMO into inner core
How is acute promyelocytic leukaemia caused by PML body mutations?
- forms reciprocal translocation within RARalpha genes
- loss of PML bodies
- hybrid altered protein
- binds & blocks transcription & differentiation
- accumulate immature granulocytes
What is the role of PML bodies?
3 main groups
- nuclear storage for accumulated proteins
- catalytic surfaces to be post-trans mod
- active sites for e.g. chromatin regulation
How are PML bodies involved in apoptosis & senescence?
- regulate p53- dependent apoptotic & cellular senescence pathways induced by stress
- recruits cell proteins to PML bodies - post trans mods, activate p53
- inhibit MDM2
How are PML bodies involved in virus infection?
targeted by viruses to:
1) viruses do not want PML bodies to initiate host response against virus
2) release proteins within PML body - enhance virus replication
