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"window of opportunity"
- few hrs after replication (if DNA pol repair mech fail) to repair the mismatch mut
- due to A base in GATC sequences in DNA usually becoming methylated several hrs after replication...quindi DNA is momentarily hemimethylated (parental DNA is methylated and daughter strand is not...yet)
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mismatch repair
- 1. finding mismatch: prot scan new DNA looking for mismatch bulges
- 2. removal: methyl on parental DNA directs enz to remove DNA on strand w/ mismatch/non methyl
- 3. repair: gap created; DNA pol makes new DNA segment and DNA ligase acts
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Xeroderma pigmentosum (XP)
disease due to mut in genes encoding components of nuc excision repair pathway; thymine dimers not repair and DNA damage persists in replication resulting in mut
mut DNA mediates carcinogenesis (act of oncogenes?)
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Hereditary, non-polyposis colon carcinoma (HNPCC)
- (lynch syndrome); due to deficiency in hMSH2 and hMLH1 genes encoding proteins of methyl directed mismatch repair sys...unrepaired mut...lots cell growth
- increased risk for cancer (esp colon)
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Fanconi's anemia
Ataxia-telangiectasia and Bloom's syndrome
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Fanconi's anemia symptoms
low WBC, RBC, platelets, increased genomic instability, increased risk of cancers, high prob of unprogrammed chrom translocations and recombinations
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Ataxia-telangiectasia
defects in enz that normally repair dsDNA breaks (phosphodiester bonds)
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Bloom's syndrome
defect in DNA ligase
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Fanconi's anemia treatment
avoid ionizing radiation, administration w/ prot like erythropoietin (to stim blood cell counts), bone marrow transplant
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sub-types of human breast cancer
mut in BRAC1 gene; prod of BRAC1 are assoc w/ prot that participate in homologous recombination repair sys that normally repairs dsDNA breaks
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types of BRAC1 gene mutations
alt splice site, nonsense mut, frameshift mut
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beta thalassemia gene mutations
promoter mut, splice site mut, polyA signal mut, non-sense, frameshift
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Burkitt's lymphoma mut
abnormal translocation btw chrom 8 and chrom 14; c-myc gene expression no longer regulated and is stim to abnormally high degree
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Becker muscular dystrophies
mut in 5'splice site of intron 19 of dystrophin gene, as a result dystrophin mRNA does not have exon 19; joining of exon 18 and exon 20 results in frameshift on transL of remaining of dystrophin mRNA
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splice site form of beat thalassaemia
G to A substitution at pos 110 in intron 1 produces a new acceptor (AG) splice site; new site used 90% and normal site used 10%...quindi normal mRNA made 10% and severe thalassaemia; BUT BOTH normal and abnormal mRNA produced
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Myotonic dystrophy symptoms
inherited; myotonia, cardiac arrhythmia, cataracts, male balding, male infertility, endocrinopathies
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myotonic dystrophy biochemistry
- amplification of GCT (at 3' end outside coding region) in myotonin prot kinase gene
- normal ppl-5-30 copies, abnormal ppl 50-100
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fragile X
amplification of CGG in 5'UTR; mental retardation in male
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missense beta globin
- occurs in AA 6
- GAG (glu) to GTG (val)
sickle cell
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nonsense beta globin
stop codon after AA 7
beta thalassaemia (anemia)
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frameshift beta globin
deletion of T reside in Thr codon
beta thalassaemia (anemia)
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trisomy 21 category frequencies
- whole-chrom>partial
- microtrisomies
- triplication of single genes or functional DNA element
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DS symptoms
mental retardation distinctive physical appearance, more likely to have acute megakaryocytic leukemia
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chrom 21 gene prod func
DNA BP, TF, nuclear and PM prot, STP
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DS biochemistry
coding and non-coding genes are over expressed; over expression of subunits of multimeric prot complexes (nucleosomes) lead to abnormal structure and function
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Burkitt's lymphoma
due to unprogrammed site-specific chrom transL
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CML
transL btw 9 and 22 which gives two new chrom; smr chrom is called Philadelphia
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Philadelphia chrom
smr chrom in CML transL; encodes a fusion prot btw portions of bcr (breakpoint cluster region) and abl (gene coding for tyrosine kinase); stim cell division
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