Chromatin biology lecture 14

Question 1

Genome instability syndromes

Answer 1

• XP, AT
• Null mutations in subset of DDR genes → embryonic lethality
• DDR critical as defects x compatible w/ cell survival
• Several diseases = assoc. w/ ↑ cancer risk

Question 2

Tumour progressoin

Answer 2

• 5-10% of cases= inherited, familiar cancer syndrome e.g. AT
• e.g. = Retinoblastoma = children inherit 1 WT + 1 mutant, loose 2nd → loss of heterozygosity
• Spontaneous mutation e.g. Burkitt’s lymphoma = translation of c-myc to chromosome 14

Question 3

Defective DNA repair

Answer 3

• Leads to micro-satellite instability
• HNPCC
• Gross chromosomal rearrangements, DSB
• Illegitimate room of repetitive DNA elements in HR → translocations or deletions

Question 4

Sub-optimal repair mechanism

Answer 4

• Defective DNA damage also channels DNA damage through sub-optimal repair mechanisms → genome instability
• e.g. w/o FA use NEHJ

Question 5

Telomeres, DDR + senescence

Answer 5

• Replicative senesce = spontaneous proliferative arrest of untransformed cells after a certain no of cell divisions due to shortened telomeres
• Telomerase makes telomeres
• At some point, x form T loop + have exposed ds break → DDR active → senescence
• Experiment

Question 6

OIS

Answer 6

• Limit where tumerous cell stops growing - OIS
• Call can determine they’re goring uncontrollably
• Experiment = DDR marker

Question 7

Synthetic lethality

Answer 7

• Malignant cells often loose DDR
• 2 pathways, if take away 1 survive, if takeaway both x
• E.g. exo1 + Sgs1 compensate for long range resection, 1 mutant = viable, both = not
• Chemotherapy using DSB, normal cells use NHEJ/HR, cancer cells x use HR, use NHEJ inhibitor so have no pathways

Question 8

PARP inhibitors

Answer 8

• PARPi = x do ss break repair, trap PARP at ss break
• Normally use HR + BRCA2
• BRCA2 mutated in breast cancer
• Give ParpI + can’t repair