The Nucleus
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What 3 things does compartmentalisation of the eukaryotic cell allow?
Protection of the DNA from a harsh cytosolic environment Seperates nuclear and cytosolic enzymes Provides a site for transcription
What is the largest sub-nuclear body?
The nucleolus
What is the space between the two membranes called?
The perinuclear space
What is the nuclear lamina?
A dense fibrillar network inside the nucleus composed of intermediate filaments and membrane associated proteins
What does the nuclear lamina do?
Regulates DNA replication and cell division as well as chromatin organisation and anchoring nuclear pore complexes
What are the main mutations that cause laminopathies in?
Lamin A/C and emerin (nuclear laminar associated proteins)
What is Emery-Dreifuss muscular dystrophy?
Affects cardiac and skeletal muscle. Causes joint deformaties and contractures as well as muscle wasting
What is Hutchinson-Gilford Progeria syndrome?
A disease where the physical aspects of aging are accelerated, most patients have a point mutation in the LMNA gene. Translation of lamin A lacking 50 amino acids. Causes mechanical defects, thickening of the lamina, loss of heterochromatin and increased DNA damage increasing susceptibility to cancer.
What is constitutive heterochromatin?
Never expressed
What is the NPC freely permeable to?
Proteins smaller than 40kDa
Describe the nuclear pore complex
8 composite rings of proteins at the cytoplasmic surface and inner surface Connected by spoke proteins From the outer ring there are 8 filaments emanating into the cytoplasm. Membrane embedded section is associated with nuclear lamins.
What are the 5 stages for nuclear import?
• NLS recognition by importin complexed to Ran • Binds nuclear pore protein • Complex is translocated by sequential binding • GEF exchanges RanGDP for RanGTP releasing the protein • Importin-Ran/complex is re-exported and GAP hydrolyses GTPRan for GDPRan
How many binding sites does importin a have and what are they?
2 Monopartite Bipartite
What recognises NESs?
Exportins
What is Nup214 and what happens if it is mutated?
Facilitates export of NES bearing cargo Mutation can lea to accumulation of proteins in the nucleus
what is Triple A syndrome?
Mutations in ALADIN (NPC component) Affects nuclear import of proteins involved in protecting DNA under oxidative stress Causes mental retardation and autonomic dysfunction
Give 3 viruses that bind NPCs
• HBV • HSV • Adenovirus
How does bulk mRNA exit the nucleus?
RNA splicing recrutis hTREX which is a complex of 20 proteins that marks the nuclear RNA for export and makes it stable which is squeezed through the pore
What are mutations in hTREX associated with?
High grade tumours A mutation enhances the formation of R loops (halt transcription and cause DNA damage), makes DNA-RNA hybrids when RNA binds a new DNA template