DNA repair disorders Flashcards
Helicase
enzyme that unzips the double stranded DNA for replication
binds at OriC (origin replication)
Topoisomerase
enzymes that relieve supercoiling problem by making single strand cuts in DNA to relieve twisting
Primase
places RNA based template for DNA polymerase to extend
DNA ligase
joins Okazaki fragments
topoisomerase inhibitors
stop replication in rapidly dividing cells.
fluoroquinolones (cipro)
campothecin compounds - topotecan, etoposide (chemo)
Chain terminators
remove 3’ hydroxyl group so that reverse transcriptase cannot add new nucleotides - inhibits replication of HIV
AZT (for HIV)
acyclovir
telomerase
adds 6 base-pair repeat to the ends of DNA so that an RNA primer can be placed and the DNA can be transcribed by DNA polymerase rather than being lost every time the DNA is replicated
active in stem cells and cancer cells
where is telomerase absent/why?
absent in terminally differentiated non-dividing cells - no DNA replication to help with
Dyskeratosis congenita features
dysplastic nails, white patches in mouth, hyper/hypopigmentation, alopecia, bone marrow failure, myelopysplasia, squamous cell cancers
Dyskeratosis congenita molecular basis
mutations in TERT and TERC and other telomere components - causes shortening of telomeres that worsens with each generation
nucleotide excision repair
removal and replacement of nucleotide(s)
used for bulky lesions caused by UV light, smoke, PAH exposure
mutations in NER genes cause xeroderma pigmentosum
Base excision repair
fixes non-standard bases or abasic sites one base at a time
usually fixes uracil bases in DNA as a result of deamination of cytosine
mutations in MUTYH (adenine glycosylase cause colon CA and polyps
xeroderma pigmentosum
extreme sun sensitivity
freckle-like pigmentation
skin cancers within the first decade of life
mutation in nucleotide excision repair
mismatch repair - what is it, what are the steps, what is the associated disease?
excises and replaces base pairs incorrectly put into the double helix that cause DNA to have a loop/bump in it.
MSH2/MSH6 bind mismatch -> MLH1/PMS2 bind and nick DNA -> nick extended by exonuclease, gap filled by polymerase, sealed by ligase
inherited mutation = Lynch syndrome
Lynch syndrome
autosomal dominant disorder which presdisposes affected people to carcinomas (esp of the colon)
requires 2nd hit to become active
microsattelite instability
microsattelite instability
hallmark of Lynch Syndrome
caused by failure to repair replication slippage at repeated sequences, resulting in changed # of repeats in DNA of tumor cells
methods of double-strand break repair - what are they and what do they have in common?
non-homologous end joining
homologous recombination
both involve extensive phosphorylation of histones at the site of damage
non-homologous end joining
simply joins broken ends together
can lead to loss of sequence
eliminates free DNA ends rapidly
error prone
homologous recombination
uses another DNA molecule with homology (usually a sister chromatid) as template for repair
more accurate than non-homologous end-joining
leads to disease if damage occurs to normal gene and is repaired with a mutant template
how do cancer cells continue proliferating without shortening telomeres?
activate telomerase
hMutSa
recognizes single mismatches for mismatch repair
hMutSB
recognizes insertion/deletion loops resulting from replication slippage for mismatch repair
when else is homologous recombination used, and what diseases are associated with errors?
gametogenesis for meiotic recombination
errors occur when chromosomes out of alignment in presence of repeat sequences - leads to Williams and CATCH-22 syndromes
direct reversal DNA repair
damage reverses without cleavage of the DNA backbone
when bases are alkylated, repair methyltransferases transfer the alkyl group to themselves - irreversible and “suicidal” repair
ataxia telangiectasia
double strand break repair syndrome
cancer and neurodegeneration
molecular basis of anticipation
triplet repeats are hard to copy due to slippage - the longer the repeat, the more likely slippage will occur
EX triplet repeat expansion disorders
Fragile X
Myotonic dystrophy
Huntington’s Disease
Fragile X
clinical features: protruded chin, mental retardation, large testicles
affected when greater than 200 triplet repeats
the expansion is not in the protein coding part of the gene, but rather, is up stream and causes FMR1 protein not to be expressed.
FMR1 is essential for normal cognitive development.
Myotonic dystrophy
clinical features: gradually worsening muscle loss and weakness
affected range 50 (mild) to 5000+ (severe, congenital)
long mRNAs form aggregates
Huntington’s disease
clinical features: mood changes, abnormal gait, progresses into dementia.
36-121 triplet repeats to be affected
polyglutamine tract in Huntington protein - creates sticky aggregates, which increase the degradation rate of neurons
