B2.033 DNA Repair Mechanisms Flashcards
what is the difference between DNA damage and DNA mutations?
damage is routine
mutations come from unrepaired damage and become a permanent part of the genome
what is a somatic mutation?
only affects individual
what is a germline mutation?
mutation in cells that produces gametes, every cell of offspring will have mutation
what are the 3 steps of DNA lesion repair?
- recognize the lesion
- remove the lesion
- fill in the gap
how are lesions recognized?
marked by protein binding and/or chromatin modification
proteins that can recognize these markers surveil the genome (PARP1)
what are the two types of simple DNA lesion repair?
- base excision repair
2. mismatch repair
what is base excision repair?
damaged base recognized by DNA glycosylase that mediated base removal
nuclease, polymerase, ligase repair
what is mismatch repair?
mismatch and single nucleotide insertion/deletion
triggers single strange incision
nuclease, polymerase, ligase repair
what is HNPCC/Lynch Syndrome?
hereditary nonpolyposis colorectal cancer
characterize HNPCC
autosomal dominant
60-80% lifetime risk of CRC
elevated risks of other cancers
congenital absence of any 1/4 proteins involved in mismatch repair
what are two types of complex DNA lesion repair?
- nucleotide excision repair
2. interstrand cross-link (ICL)repair
how does nucleotide excision repair work?
recognized helix distorting lesions
20-30 nt region removed
polymerase, ligase repair
how does interstrand cross link (ICL) repair work?
- recognize stalled replication forks
- necessary factors recruited and activated
- homologous recombination repair
what is a nucleotide excision repair pathology?
xeroderma pigmentosum (XP)
what is an ICL pathology?
fanconi’s anemia
loss of any one of the proteins involved (homozygous in 1 of 13)
what are the types of double strand break repair? which is better?
- homologous recombination (this one rox)
2. non homologous end joining (this one sux)
characterize homologous recombination repair of DSBs
error free
occurs in S and G2 phases of cell cycle
ssDNA invased undamaged homologous template
BRCA1, BRCA2/FANCD2 involved
what syndromes result from defects in homologous recombination repair pathways?
chromosome instability syndromes
fanconi’s anemia
characterize non-homologous end joining repair of DSBs
- KU protein binds ends
- recruits/activates protein kinase
- kinase recruits/activated end processing enzymes
- ends join and are filled in
wrong ends join a lot bc NHEJ is trash
what are 3 ways to become unable to repair lesions?
congenital deficiency
somatic mutation
epigenetic silencing of gene coding for repair protein
why are cancer cells reliant upon functional DNA repair mechanisms?
even cancer cells can only tolerate so much DNA mutation before they cease to be able to function like a normal cell and die
how are BRCA1 and BRCA2 involved in DNA repair?
involved in homologous repair
recognizes and prepares DNA ends for strand invasion
without these genes functioning, you get more trash NHEJ repair
what does PARP1 do?
binds to nicks/breaks and chemically modifies nearby chromatin so that repair can be completes
how do PARP1 inhibitors work?
prevent repair of DNA lesions, leading to dsDNA breaks
why are BRCA1 and BRCA2 neg breat cancers particularly sensitive to PARP1 inhibitors?
PARP1 inhibitors lead to dsDNA breaks
cant repair these correctly without BRCA1,2
have to resort to NHEJ trash mechanism and then ur unstable and die
