Craniofacial abnormalities Flashcards
Neurocristopathies
Neurocristopathies are congenital malformations arising from defects in the development of neural crest cells
Mutations in genes encoding ribosome proteins or involved in ribosome production can cause at least two related craniofacial abnormalities
Treacher- Collins syndrome and Diamond Blackfan Anemia.
Mutations in genes encoding ribosome proteins or involved in ribosome production can cause at least two related craniofacial abnormalities
Treacher- Collins syndrome and Diamond Blackfan Anemia.
At the cellular level, abnormal neural crest cell development can result in…?
- not enough cells being formed, disruptions in cell migration, and failures of cells to produce the appropriate gene products necessary for differentiation
Ribosome production
Nucleoli form around NORs that contain tandem repeats of the 45S rDNA sequence (18S, 5.8S, 28S) which is transcribed by RNA pol I (occurs in the nucleolus)
the 5S sequence is transcribed by RNA pol III (occurs on chromosome 1)
What are ribosomes and what are they made out of?
large macromolecular assemblies of proteins with ribosomal RNA (rRNA). Each ribosome contains 4 rRNAs plus around 85 different ribosomal proteins. These assemblies are divided into two subunits, the 60S large subunit and the 40S small subunit, which are built separately.
Where can mature ribosomes be found? free in the cytoplasm or attached to the endoplasmic reticulum
Mature ribosomes can be found free in the cytoplasm or attached to the endoplasmic reticulum
What is the role of the ribosome?
translate RNA into protein
Describe 45S rRNA transcription
- UBF bings to the UCE and core elements, recruits SL1
- UCE and core elements are brought together
- RRN3/TIF-1A (transcription initiation factors) bind
- Pol I binds and transcription begins
- UBF and SL1 remain in place, loading more POL 1
Describe 45S rRNA transcription
- UBF bings to the UCE and core elements, recruits SL1
- UCE and core elements are brought together
- RRN3/TIF-1A (transcription initiation factors) bind
- Pol I binds and transcription begins
- UBF and SL1 remain in place, loading more POL 1
Describe the promotor region of the 45S rRNA
Promoter: no TATA box, UCE at -200 to -107, Core promoter (CP) at -45 to +20
What is SL1?
TBP (TATA binding protein) plus three TAFs
What transcription factors bind in 45S rRNA transcription?
RRN3/TIF-1A
What transcription factors bind in 45S rRNA transcription?
RRN3/TIF-1A
What pathway specifically monitors the process of rRNA transcription?
The nucleolar stress response, which works through p53
How does the nucleolar stress response normally operate when everything is fine?
The MDM2 protein binds to p53 and ubiquitinylates it with an E3 ligase domain at its C terminus. This leads to the degradation of p53 by the proteosome.
What happens when ribosomal rRNA production is not keeping up with ribosomal protein production?
unincorporated ribosomal proteins accumulate. These will bind to the central acidic region of MDM2 and prevent it from ubiquitinylating p53. Hence, p53 levels build up and stimulate the expression of p53 response genes, which triggers apoptosis of the cell.
What do you expect happens to p53 if it is ubiquitinylated?
p53 will be degraded by the ptoreosome
