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CHEM141 > DNA Structure, Storage, Replication And Repair - Done > Flashcards

DNA Structure, Storage, Replication And Repair - Done Flashcards

1
Q

How many base pairs per DNA helical turn?

A

10 - 10.5

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2
Q

How wide are the minor and major groves in DNA respectively?

A

Minor groove - 1.2nm wide

Major groove - 2.2nm wide

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3
Q

What’s the significance of the major groove?

A

The edges of bases are more accessible and lots of enzymes use this as a binding site - transcription factors

Also a target for medicinal chemists to exploit

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4
Q

What is the mechanisms of intercalating drugs on DNA?

A

Planar (aromatic or heteroaromatic) systems slip between the layers of nuclei acid pairs and disrupt shape of helix

Affects enzyme binding

Often show preference for minor or major groove

Intercalating can inhibit topoisomerases

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5
Q

What is proflavine and what does it treat?

A

Intercalating antibacterial drug - used in WW1 to treat deep face wounds

Completely ionised at physiological pH - ion-ion pair anchor drug in

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6
Q

What does doxorubicin treat?

A

Anticancer drug

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7
Q

Where does doxorubicin bind?

A

At the major groove in DNA, charged amino group acts as anchor

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8
Q

Why is doxorubicin considered a Topoisomerase ll poison?

A

Because intercalation prevents normal action of enzyme

Crucial to replication and mitosis

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9
Q

Briefly describe the process of gene expression

A

Cell transcribes the nucleotide sequence of a gene into an RNA molecule.

Cell then transcribes RNA molecule into amino acid sequence of a protein.

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10
Q

Define what a gene is

A

A gene is a segment of DNA that contains the instructions for making a particular RNA and/or protein.

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11
Q

What is an organisms karyotype?

A

The full set of chromosomes

Karyotype of humans is 46 chromosomes

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12
Q

What is interphase?

A

Cell is actively expressing its genes, DNA can replicate and complete gene expression to proteins.

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13
Q

What is M-Phase?

A

The mitotic phase where chromosomes become more densely packed - cell division

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14
Q

What’s significant about the structure at the telomere?

A

Higher concentration of G-C base pairs - chemical knot tying the ends

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15
Q

What’s the purpose of the centromere?

A

Attaches duplicated chromosomes to mitotic spindle

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16
Q

Why are genes found far from the centromere?

A

To reduce error

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17
Q

What’s the complex of nuclear DNA with histone and non-histone proteins called?

A

Chromatin

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18
Q

What is a nucleosome?

A

Nucleosomes contain DNA wrapped around a protein core of 8 histone molecules - 2 molecules each of histones H2A, H2B, H3 and H4

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19
Q

How many base pairs are in a histone octamer?

A

147 base pairs - 1.7 turns of DNA in a left-handed coil per histone octamer

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20
Q

What are the properties of histones?

A

Long N-terminal tail

High proportion of +ve amino acids - Arg and Lys

  • Positive charge helps histones bind tightly to -vely charged sugar-phosphate backbone
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21
Q

What’s the role of topoisomerase l?

A

Relieve torsional stress of supercoiled DNA - only cleaves 1 strand

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22
Q

What’s the role of topoisomerase ll?

A

Cuts both DNA strands which are pulled apart to allow second strand to pass through - strands are then resealed

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23
Q

By what mechanism does topoisomerase ll break the sugar-phosphate backbone?

A
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24
Q

How do intercalating drugs interfere with topoisomerases?

A

By preventing replication transcription [artly by inhibiting topoisomerases function

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25
Q

What does camptothecin treat?

A

Cancer - topoisomerase poison

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26
Q

What’s the method of action for camptothecin?

A

Stabilises the cleavable complex formed between DNA and topoisomerase l

Cancer cell dies

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27
Q

What are fluoroquinolones?

A

Topoisomerase poisons

They’re synthetic agents that target topoisomerase lV, bacterial homologues

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28
Q

What is the method of action of fluoroquinolones?

A

They inhibit replication and transcription of bacterial DNA by stabilising the bacterial topoisomerase - DNA complex

Binding site only appears after the DNA has been ‘nicked’ and DNA strands are ready to be crossed over

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29
Q

How do fluoroquinolones lock to the enzyme?

A

Have a carboxylic acid which becomes charged at physiological pH as well as 2 R groups on opposite side

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30
Q

Why are chemical modifications to histone tail important?

A

Because modifications control which genes are switched on/off

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31
Q

What does a methyl group at K 9 mean on a H3 histone tail?

A

Heterochromatin formation, gene silencing

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32
Q

What does a methyl at K 4 and acyl at K 9 mean?

A

Gene expression

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33
Q

What does a phosphate at S 10 and acyl at K 14 mean?

A

Gene expression

34
Q

Define epigenetic inheritance

A

The transmission of a heritable pattern of gene expression from one cell to its daughter cells that does not involve the DNA sequence

35
Q

How can epigenetic transmission occur?

A

Parental cell divides, leaving half of the modified nucleosomes for each daughter cell.

Proteins that recognise the same modifications they catalyse can then restore the parental modification pattern of nucleosomes - helping eukaryotic cells to ‘remember’ whether the gene was active

36
Q

How many bases are wrong in the entire process of cell division?

A

1 - 3 letters wrong

37
Q

What is structural important at replication origins?

A

Stretches of DNA rich with A - T

38
Q

How many replication sites are in the human genome?

A

10,000 replication origins

39
Q

What protein opens the DNA helix?

A

DNA helicase

40
Q

What way can DNA only be synthesised in?

A

5’ —> 3’ direction

41
Q

What direction is DNA always read in?

A

ALWAYS reads 3’ —> 5’ direction

42
Q

What has DNA Polymerase evolved to do?

A

Evolved to use nucleotide triphosphates as substrates which are paired to the base in the template strand to grow the chain in 5’ —> 3’ direction

43
Q

How is proofreading achieved?

A

Polymerisation and proofreading steps are tightly coordinated - happening in different domains

If incorrect base is paired then it is removed and correct nucleotide is added and synthesis continues

44
Q

What’s the proofreading domain known as?

A

A nuclease domain - E

Results in error in 1 in every 10 million base pairs.

45
Q

What is the strand that can grow in 5’—>3’ direction called?

A

The leading strand

46
Q

What is the strand that can grow in 3’—>5’ direction called?

A

The lagging strand

Grown discontinuously using back stitching - forms Okazaki fragments

47
Q

What’s the function of DNA primase?

A

Creates an RNA primer - short sequence which provided a base-paired 3’ end as a starting point for DNA polymerase.

48
Q

What’s the function of DNA polymerase?

A

Helps grow the chain from the primer

Will form Okazaki fragments if on lagging strand template

49
Q

What’s the function of nuclease enzymes?

A

Once the new Okazaki fragment reaches the primer of a previous fragment, nuclease cleaves off the primer

50
Q

What’s the function of repair polymerase?

A

Replaces primer section with DNA

51
Q

What’s the function of DNA ligase?

A

Joins sections of DNA together

52
Q

What function group do all topoisomerase poisons possess?

A

A lactone ring - cyclic ester

53
Q

What are chain terminating drugs?

A

Drugs that act as false substrates and are incorporated into the DNA chain during replication

Chain can no longer be extended once added

54
Q

What must chain terminating drugs have?

A

A triphosphate group

A structure that makes it impossible for further building blocks to be added - No 3’ OH group to build from

Also must be recognised by DNA template and interact with nucleic acids.

55
Q

What drug is used to treat herpes? How does it achieve this?

A

Acyclovir - antiviral agent

Is a substrate for viral thymidine kinase but not human - converting it to its monophosphate.

56
Q

Why can the triphosphate not be used in chain terminating drugs?

A

Cannot be used because drug would be too polar to enter cells

57
Q

After the mismatch repair mechanism what’s the overall efficiency of DNA replication?

A

1 error in every billion base pairs

58
Q

How does sickle-cell anemia occur?

A

Occurs as a result of one uncorrected error in the gene for Beta-globin

59
Q

What’s the significance of thymine dimers?

A

Ultraviolet radiation causes this

Changes the structure of DNA - meaning those who cannot correct this have to avoid sunlight and are very susceptible to skin cancers

60
Q

What two reactions are the most common to create serious DNA damage in cells?

A

Depurination - loses purine as polymerase skips over it - frameshift

Deamination - cytosine amine is replaced by ketone - forming T not G as product

61
Q

How does the mismatch repair system recognise a mistake?

A

Because a mutation can alter the secondary structure of DNA

Hence repair proteins can recognise this

62
Q

What’s the mechanism for the mismatch repair system?

A

1 - nuclease protein specific to the damage cleaves the phosphodiester linkages of the damaged nucleotide

2 - repair DNA polymerase replaces the gap created with correct nucleotide

3 - ligase enzyme joins the sections together

63
Q

What do alkylating and metallating agents do?

A

They often form covalent bonds to nucleophilic centres in DNA with their highly electrophilic groups.

This can disrupt/prevent replication and transcription - useful against cancer

64
Q

What are possible toxic side effects of alkylating and metallating agents?

A

Protein alkylation

65
Q

How are inter-strand crosslinks formed?

A

React with nucleic acid base on each chain of DNA duplex

This crosslinks the strands - disrupting replication and transcription

66
Q

How are intracellular-strand crosslinks formed?

A

Link two nucleophilic groups on the same chain

That DNA portion then becomes masked from enzymes - stopping replication

67
Q

What does a drug need to form inter/intra-strand crosslinks in DNA duplexes?

A

TWO alkylating groups

68
Q

How can you find basic nitrogen’s on nucleic acids?

A

Nitrogen’s that have lone pairs orthogonal to the ring - not involved in aromaticity

69
Q

How does miscoding lead to altering protein structure and function? Where can this be useful?

A

Guanine exists in keto form - though when alkylated it exists in enol form

This makes it more likely to bind to thymine - useful in anticancer and antiparasitic drugs

70
Q

What anticancer drug contains a aziridinium ion?

A

Nitrogen mustards, Chlormethine - crosslinks DNA so stop replication

(Aziridinium ion HIGHLY electrophilic)

71
Q

What do nitrosoureas treat and how do they function?

A

Anticancer drug

Nitrosoureas decompose spontaneously in the body to form 2 active compounds

72
Q

Give an example of a nitrosourea?

A

Carmustine

Lomustine

Streptozotocin

73
Q

What do the active compounds of nitrosoureas do?

A

One carbamoylates lysine residues - inactivating DNA repair enzymes

Other causes alkylation on O6 of guanine and N3 of cytosine

74
Q

What is Busulfan and what does is do?

A

Anticancer drug

Causes inter-strand crosslinking between guanine units.

75
Q

What’s the general structure of Busulfan? What’s its role?

A

Busulfan has 2 sulfonate groups at either end of a 4 carbon chain

Sulfonate groups are good leaving groups and so can crosslink 2 DNA strands, stopping replication

(Inter-strand crosslinking)

76
Q

What anticancer drug is neutral and unreactive?

A

Cisplatin

77
Q

How is cisplatin activated and what’s its function?

A

Activated within cells by aquation

Intra-strand crosslinking — N-7 and O-6 positions of adjacent guanine molecules

78
Q

What is Calicheamicin Y1 and what does it do?

A

Anticancer agent that cuts DNA strands and prevents DNA ligase from repairing the damage

79
Q

How does Calicheamicin Y1 act as a chain cutter?

A

It creates radicals on DNA structure that react with oxygen to form peroxy species and DNA chain fragments

80
Q

Where does Calicheamicin Y1 bind?

A

Binds at the minor groove in DNA helix

81
Q

What compounds work the same way as Calicheamicin Y1?

A

Bleomycins and podophyllotoxins

CHEM141 (12 decks)

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