16. ageing biology 2 Flashcards
name three types of DNA repair mechanisms
- nucleotide excision repair
- base excision repair
- homologous recombination
- non-homologous end joining
what is nucleotide excision repair used for and describe the process
bulky adducts
>removal of a short single strand DNA segment, DNA polymerase uses other strand as template, ligation by DNA ligase
what is base excision repair used for and describe the process
ssDNA breaks and small base damage
>DNA glycosylases which recognises and removes damaged base, AP site cleaved by exonucleases, DNA polymerase uses other strand as template, ligation by DNA ligase
what is homologous recombination used for and describe the process
interstrand cross links and double strand breaks
>nucleotide sequences are exhcnaged between two similar or identical DNA molecules
what is non-homologous end joining used for and describe the process
double strand breaks
>non-homologous end joining joins broken chromosome end in a manner that does not require sequence homology
what is mismatch repair used for and describe the process
mismatches
>nucleotide excision of mismatched base and a few surrounding bases, DNA polymerase fills in gap
what is used to overcome telomere shortening?
telomerase reverse transcriptase/RecQ
sometimes damage is not repaired, why might this happen?
UV induced cyclobutane pyrimidine dimers often ignored because they look like normal DNA
which DNA repair process can be coupled with transcription?
nucleotide excision
what may happen is DNA repair is faulty? and what disease is this seen in
cancer or stall in polymerase which kills cells - these are seen in progeroid syndromes
name a disease where faulty DNA repair leads to premature ageing? and what is this disease?
Cockayne syndrome
>a rare segmental progeroid syndrome
what are the symptoms of Cockayne syndrome ?
growth failure, microcephaly, sensitive to sun, eye disorders and premature ageing
what is the mean lifespan of Cockayne syndrome ?
12 years
what causes Cockayne syndrome ?
mainly due to defects in CSB gene
>transcription coupled excision repair protein
rest due to defects in CSA - involved in the same process
>also component in ubiquitin ligase complex (might ubiquitinate CSB)
what can people with Cockayne syndrome not repair? and what does this lead to?
oxidative induce damage to DNA bases in the strands of DNA that are being transcribed i.e. transcription coupled DNA repair
>blocks in transcription which leads to apoptosis
what has been seen to recuse premature ageing in Cockayne syndrome?
high fat diet in mice which activates sirt1
in general what accumulates as we age and what does this lead to?
DNA damage
can kill or senesce cells
what are senescent cells linked to? and what does this lead to?
inflammatory signals
chronic inflammation is associated with ageing and plays a causative role in age-related disorders such as cancer
what does increased levels of p53 trigger?
a senescence response
what happens to guanine when ROS attack it and what results from this?
it forms 8-oxo-guanine
>this can pair with cycteine and adenine
what type of therapy can induce premature ageing?
chemotherapy and radiotherapy
what does decreased HDAC1 function result in in the brain?
more double stranded DNA breaks
- neural death and neurodegeneration
name two class III NAD+ dependent HDACs? and what is their secondary function?
SIRT1 and SIT6
>required for efficient double stranded DNA break repair
what happens when people lack the enzyme SIRT6? and what do KO mice for this display?
they are not efficiently repairing oxidative damage
>several progeroid symptoms and early death
