DNA repair Flashcards

1
Q

what do cancer cells display

A

altered behaviour

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2
Q

what is the system by which cells become cancerous?

A

normal cells become activated by oncogenes into pre-cancerous cells, which then lose rumour suppressor function and turn into benign neoplasia, then cell functions become altered and they become malignant neoplasia cancerous cells

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3
Q

what is neoplasia

A

tissue composed of cells with the ability to grow beyond their normal confines

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4
Q

what does tumorigenesis require

A

alterations in cell function

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5
Q

define hyperplasia

A

too many cells

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6
Q

define dysplasia

A

abnormal looking cells

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7
Q

define adenoma

A

a benign tumour

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8
Q

define carcinoma

A

a malignant tumour

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9
Q

what are the mutations involved in cancer development

A

initiating mutation - first clonal expansion, second mutation - second clonal expansion, third mutation - third clonal expansion and fourth mutation - fourth clonal expansion
etc.

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10
Q

explain what tumour elevation is and what it does to populations of cells

A

tumour elevation is not linear but is dynamic and gives rise to populations of cells with distinct proliferative advantage

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11
Q

what does oncogene activation result in?

A

precancerous state which can be accompanied by increased DNA damage

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12
Q

how are pre-cancerous states kept under control

A

by checkpoints
these prevent proliferation of these cells

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13
Q

what does loss of tumour suppressor function (linked to failure of cell cycle checkpoints) enable

A

pre-cancerous cells to proliferate

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14
Q

how do proliferating tumour cells evolve

A

through mutagenesis and acquire altered cell function

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15
Q

what do tumour cells often exhibit changes in?

A

chromosome number and structure

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16
Q

define mutations

A
  1. a change in the structure of a nucleotide sequence, often, in a gene
  2. the altered sequence or gene resulting from such a change
  3. a change in the karyotype (chromosomal mutation)
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17
Q

how does UV (sunburn) cause cancer

A

2 adjacent nucleotides become linked

18
Q

how can be bases be lost

A

due to attack by water molecules (depurination/depyrimidination) leaving a non-coding lesion
these non-coding lesions result in coding changes after DNA replication

19
Q

what can deamination of different bases lead to

A

the generation of non-coding bases that cannot pair with normal bases during replication.

20
Q

what does energy production in mitochondria produce

A

highly reactive oxygen species (ROS)

21
Q

what can ROS cause

A

DNA breaks and oxidised bases

22
Q

what does oxidation of guanine to 8-oxo dG cause

A

mispairing during replication and therefore to genetic change

23
Q

what does methylation of bases cause

A

mispairing of bases during replication leading to genetic change

24
Q

what is 5-me cytosine

A

a normal tolerated form of methylation that plays a role in gene regulation during transcription

25
Q

what does replication require

A

accurate duplication of many billions of bases in order to avoid causing mutation - therefore many opportunities for mutation

26
Q

what does DNA polymerase (which duplicated genomes) have

A

a proof reading function which can identify mis incorporated nucleotides which can be removed and replaced with the correct nucleotide

27
Q

what does failure to perform proofreading cause in vivo (mice)

A

increased death in mice as a consequence of elevated tumour formation

28
Q

what are mispairs that occur in the genome and are not corrected by proof reading recognised by?

A

the mispair repair pathway (MRP)

29
Q

what identifies a mismatch in the MRP?

A

a complex of MutS and MutH (MutSH)

30
Q

what does MutSH do once it identifies a mismatch

A

slides (translocates) along DNA until it reaches a nick/gap often present on newly synthesised DNA strand during replication - this helps recruit Exo1 nuclease

31
Q

what does Exo1 nuclease do

A

digests one strand of DNA from the nick to the mispair onto which loads single strand binding protein RPA (replication protein A)

32
Q

what does MutSH do

A

dissociates and polymerase delta/epsilon synthesised complementary DNA to fill the gap and remove the mismatch

33
Q

how is base damage repaired

A

by the removal of the damaged base through the action of a glycosylase (eg uracil DNA glycosylase)

34
Q

what does AP (apurinic/apyrimidinic) exonuclease do

A

its recruited 5’ to the abasic site and nicks the sugar phosphate backbone of DNA - 3’ to the a basic site a dRP lyase nicks the backbone to remove the abasic flap and the gao is filled in by the action of a polymerase and DNA ligase

35
Q

what are pyrimidine dimers (nucleotide damage) recognised by?

A

the XPC protein

36
Q

where is the lesion containing strand nicked

A

either side by a complex of XPF and ERCC1 (5’ side) and XPG (3’ side) approximatly 23 nucleotides apart in human cells

37
Q

what happens to nicked regions of DNA

A

it is unwound and removed through the action of the TFIIH sybunit (containing XPB and XPD helicases) of RNA polymerase II - the gap is refilled by DNA polymerase and DNA ligase

38
Q

what are double stranded DNA breaks repaired throughout the cell cycle by

A

NHEJ

39
Q

what are breaks processed for

A

to be made compatible for joining a ligase through the action of proteins that tether the broken DNA ends Ku70/80 complex, nucleases such as Artemis and the MRN complex (Mre11/Rad50/NBS1) which nibble unligatable ends and polymerases which ‘fill-in’ ends until they can be rejoined by DNA ligase IV. this process can lead to loss/gain of genetic information and so is error prone

40
Q

what happens if Ky70/80 is not avaliable or ends are unable to be processed for joining by canonical NHEJ

A

then ends may undergo DNA resection by CtlP and MRN to reveal complementary sequences that can pair to tether broken ends for joining by ligase - this can lead to extensive deletions