L10, MMR, Cockayne etc Flashcards
1
Q
Clinical features of CS:
A
- Severe developmental disorder
- Low birthweight, growth failure, short stature, premature aging
- Severely deficient neurological development, leading to learning delay
- Photosensitive skin
- No UV-induced skin cancer
- AR inheritance
2
Q
Cellular features of CS:
A
- Sensitive to UV and other DNA damaging agents
- However, they have normal repair synthesis and incisions at pyrimidine dimers
- Defective recovery of normal semi-conservative DNA synthesis following UV damage, as well as recovery of RNA synthesis; defective TCR
3
Q
Name and outline the two modes of NER:
A
- Global excision repair (as in XP patients); slow, operates across whole genome, mainly prevents mutations
- Transcription coupled repair; repairs transcription blocking damage in transcribed strands of expressed genes; fast, functions to prevent cell death
4
Q
How is repair machinery recruited in GGR vs TCR:
A
- GGR: Damage recognised by XPC or XPE -> specificity conferred
- TCR: Stalling of RNA PII at damage recruits repair machinery -> broad specificity
5
Q
Components of TCR:
A
- CSA and CSB commonly mutated in CS patients (90%)
- CSA interacts with RNA PII, TFIIG and CSB
- CSB is a member of SWI/SNF family protein (chromatin remodelling); associates with RNA PII, TFIIH and PARP
6
Q
Why don’t CS patients have a skin cancer predisposition?
A
- Dead cells can’t form tumours; RNA PII will stall at site of damage and signal apoptosis
- Mutations are not accumulating
7
Q
Why do CS patients have such sever developmental disorders?
A
- Defect in TCR
- Brain is particularly metabolically active; lots of damage via ROS
- NER is altered in a tissue specific manner in the brain to upregulate TCR and downregulate GGR since cells are not dividing
- Damage persists, block RNA P -> extensive apoptosis
8
Q
Why do some XP patients suffer neurological abnormalities?
A
- XP-A, B, D, F and G are also involved in TCR -> similar neurological effects as in CS
- XPC and E, however are only involved in GGR
9
Q
Features of Lynch syndrome / HNPCC
A
- Most common inherited predisposition to colorectal cancer (2-3% of all colorectal cancers)
- AD inheritance with 80% lifetime risk of cancer
- Often early onset (before age 50)
- Increased risk of developing specific spectrum of other cancers including 50% lifetime risk of endometrial cancer
10
Q
HNPCC tumour cellular features:
A
- microsatellite instability
- Short 1-6 nts motids repeated 10 to 60 times
- Supposed to be stable within individuals; this is not the case here
11
Q
How does microsatellite instability arise?
A
- Results from errors as a result of slippage during replication of repeats
12
Q
MMR in yeast and bacteria:
A
- Replication errors repaired by mismatch repair e.g. E.coli MutS, MutL, MutH system
- Yeast/bacteria with mutations in MMR genes have similar instability phenotype ‘mutators’
13
Q
How does MSI phenotype come about:
A
- Behave like TSGs -> 2 hits
- First hit: inherited germline mutation
- Second hit: either LOH of wt allele of epigenetic changes to silence wt allele
14
Q
Consequences of MSI:
A
- Increased error rate for errors that are normally repaired by MMR
- Can be in the form of frameshifts
- Mutation targets: genes containing microsatellites (often TSGs e.g. TGFbeta)
15
Q
+ DNA DSB Repair deficiency example:
A
- Ataxia Telangiectasia
- ATM gene
- Leads to neurodegeneration, immunological defects, malignancy and sterility
