Bleomycins

Question 1

Bleomycins are a family of _______ abx

Answer 1

Glycopeptide

Question 2

Therapeutic efficacy of bleomycin is limited by development of ____ ______.

Answer 2

Lung fibrosis

Question 3

Cytotoxic and mutagenic effects of bleomycin thought to be related to ability to mediate both ___ ____ and ____ _____ DNA damage

Answer 3

Single stranded

Double stranded

Question 4

____ _____ and _____ _____ DNA damage requires the presence of specific _____ (a transition metal (F__ and C___), ____ and one electron reductant)

Answer 4

Single stranded
Double stranded 
Cofactors
Fe(II)
Cu(II)

Question 5

Bleomycin are a family of glycopeptide first isolated from ______ bacteria

Answer 5

Streptomyces

Question 6

Argued that ___ _____ DNA cleavage is initiated by activated metal conjugated form of bleomycin

Answer 6

Double stranded

Question 7

What are the most common outcomes of bleomycin treatment? (3 things)

Answer 7

Extended cell cycle arrest
Apoptosis
Mitotic cell death

Question 8

The whole molecule is much greater than the sum of its parts e.g the ___ between the metal and bithiazole DNA binding domain and ____ of the bithiazole moiety itself are essential for efficient dsDNA cleavage

Answer 8

Linker

Flexibility

Question 9

Bleomycin are _____ molecules that are unable to cross cell membranes by free diffusion. The ____ charged tail of bleomycin might be key to cellular uptake.

Answer 9

Hydrophillic

Positively

Question 10

Bleomycin initiate _____ cleavage at pyrimidines 3’ to a guanine in sequence specific fashion

Answer 10

SSDNA

Question 11

_____ cleavage by a single bleomycin molecule requires bleomycin reactivation and reorganisation during of after cleavage of 1st strand of DNA

Answer 11

DSDNA

Question 12

What is the key to bleomycin reorganisation? (required for _____ cleavage)

What does this allow?

Answer 12

DSDNA
Linker
Flexibility of bithiazole tail that is bound by partial intercalation

Rotation around bond in the two thiazide rings in tail of bleomycin (and other motions), make peroxide of activated drug available for interaction with 2nd DNA strand.

Question 13

What are the 4 stages of DSB repair?

Answer 13

1) Introduction of DSB
- e.g DNA damaging agent (bleomycin)

2) Nucleolytic processing
- DNA processed at site of break to yield regions of SSDNA

3) Filament formation, homology search and joint
molecule formation
- Rad51 and replication protein A, coat SSDNA to form filament that searches for seq on homologous chromosome)
- When found = initiates formation of joint molecule

4) Repaired recombinant products
- Break repaired by DNA synthesis using intact strands as template
- Repaired recombinant products are made

Question 14

Why is DSB repair more difficult than say NER?

Answer 14

More steps where things can go wrong so a more difficult repair especially when using NHEJ and BIR as they have many complex steps.