Cancer and DNA repair- 4 lectures

endogenous- spontaneous damage from defective repair etc exogenous- from radiation, sunlight etc

SSBs- 55k per cell per day

cytosine deamination depurination/depyrimidination

looking for abnormal karotypes in mutants mutational signatures- tracking specific mutations in sequences (you can do a lot of mathsy stuff out of this)

direct DNA repair enzymes. convert pyrimidine dimers into normal base pairs using photons

transfer methyl groups to cysteine- also direct DNA damage reversal

DNA glycosylase does the excision of a lesion nick is then created

short patch- repairs single BP gaps by cutting out the BP long patch- several nucleotides need to be replaced- damaged DNA is a ‘flap’ which is removed

nucleotide excision repair

detection of unpairing and abnormal DNA structure incisions made at both sides of a lesion excision w helicases DNA synthesis and ligation

a version of NER which happens during transcription- triggered by RNA Pol II detecting damage similar events to regular NER

interstrand cross-link repair

aplastic anaemia with short stature, hypogonadism, skin pigmentation Due to defective ICL DNA damage repair

DNA polymerase synthesis, hom. recomb. and NER- she’s diverse

DNA replication or transcription, or independently of other pathways

NHEJ, HR

NHEJ can occur at any point in the cell cycle, more error-prone? HR requires a sister chromatid, so is restricted to S/G2- the sister chromatid makes it more accurate

single-strand annealing double holliday junction (DHJ) synthesis-dependent strand-annealing

3’OH generation, annealing of the homologous sequence, removal of ‘flaps’ and ligation -often leads to deletions

resection, one end then ‘invades; the sister chromatin second end captured in a D-loop, 2 HJs are formed can lead to gene conversion of recombination, depending on how cleavage occurs dissolution doesn’t lead to crossing over, resolution can

resection, invasion of sister chromatid, polymerase then fills in and completes the repair with no impact on the sister chromatid

Rad51

MRN displaces recruited Ku, preventing the pathway from occuring

non-homologous end joining