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DNA Repair Flashcards

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1
Q

why does it take a long time to develop cancers

A

Takes a while to develop cancer as need quite of lot of changes to take place
Initial change needs to activate an oncogene- this is one of the few positive changes in cancer. This makes the cell PRE cancerous. Then other mutations (e.g. of tumour suppressors) to get rid of quality control mechanisms and allow cancer to form
Oncogene activation= hyperplastic = other mutations (loss of tumour suppressors)= neoplasm= acquiring functions (hallmarks)= metastasis

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2
Q

what is neoplasia

A

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

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3
Q

how do cancers acquire all the hammarks needed

A

genomic instability

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4
Q

what are the stages of cancer cell development

A 
normal
hyperplastic 
dysplastic 
adenoma (benign) 
carcinoma (malignant)
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5
Q

what does clonal expansion allow

A

multiple genetic changes confer a growth advantage onto the cancer cells - allowing best suited to survival to become dominant

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6
Q

is cancer development linear

A

no depends on the environment its in

dynamic clonal diversification in which a heterogeneous array of cancer cells develop within a tumour

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7
Q

what most often causes the mutations in cancer

A

happen as a result of normal cell processes - not due to direct carcinogen exposure

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8
Q

what are the different broad types of mutations

A

change in nucleotide sequence
altered sequence or gene resulting from such a change
change in the karyotype (chromosomal mutation)

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9
Q

what does mutagenesis require

A

cellular function (is an active process)

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10
Q

what is the role of UmuDC genes

A

helps cell actively perform mutagenesis in response to things that induce mutation (e.g. UV light) so that cells can acquire traits that enable them to become resistant to these adverse conditions and survive

UmuDC genes are involved with DNA repair but do it inaccurately so facilitate mutagenesis

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11
Q

why did the bacteria need arginine to mutate

A

as shows need cell functions (arginine used by UmuDC genes for DNA repair)
shows in order to get mutation need normal cell processes
shows mutations are an active cell process- happen by the cell not to the cell

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12
Q

if a substance is carcinogenic, what does this mean?

A

how much of it is needed to cause 50% cancer formation (in mice) over 24 months

the more mutagenic a substance is the more tumorigenic it is likely to be

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13
Q

what is the lynch between inherited diseases that affect DNA repair and cancer e.g. lynch syndrome, BRAC1 and 2, MSH6, xeroderma pigmentosum

A

many of these diseases have defects in proteins required for DNA damage repair
most cause cancer predisposition as result in genomic instability

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14
Q

what are potential internal sources of DNA damage

A

reactive oxygen sources
oxidation, alkylation, hydrolysis
replication errors

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15
Q

what creates reactive oxygen species

A

normal aerobic metabolism

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16
Q

how does UV radiation affect DNA

A

causes adjacent pyrimidine bases to covalently bond creating pyrimidine dimer
creates non coding region resulting in nucleotide miss pair

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17
Q

when does a mutation become fixed

A

mutation
replicated (misspair)
replicated again= fixed into genome

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18
Q

how does ionising radiation affect DNA

A

direct action= energy transfer, production of damaging electrons
indirect action= electrons react with water to creative chemical species e.g. free radicals that cause further DNA damage

causes energy transfer that causes both single and double strand DNA breaks
these broke ends are susceptible to cellular endonuclease that removes coding nucleotides at the site of the break
repair of this can also result in translocations

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19
Q

how does oxygen affect DNA damage

A

more oxygen present more damaged caused by ionising radiation due to organic free radicals (hydroxyl OH)

if oxygen absent then radical forms can be repaired, if oxygen present then organic peroxide RO2 formed which cannot be repaired

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20
Q

what translocation is associated with ewings sarcoma

A

chromosome 11 and 22

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21
Q

how can water damage DNA

A

DNA bases react with water in cells causing depurination (more common than loss of de-pyrimidation)
this loss of a base is non coding (abasic)= miss pair repair happens

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22
Q

what is the specific role of UmuDC genes

A

put any base in sequence to repair areas of non coding sequence that are missing bases via error prone polymerase
this creates a mutation that will either kill the cell or give in an advantage driving evolution of the cell to become resistant to whatever caused the damage

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23
Q

what do cellular deaminases do

A

de aminate bases, can transform them into guanine-> xanthine

=non coding lesion

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24
Q

what creates reactive oxygen species normally

Study These Flashcards
A

oxidative metabolism and the generation of ATP

25
how do ROS affect DNA
react with the sugar phosphate backbone causing single or double stranded breaks or can remove bases creating an abasic site OR can react with bases to create an oxidated form e.g. 8 oco guanine which pairs with adenine not cytosine= misspair (transversion mutation)
26
how does methylation affect DNA
makes none coding or misscoding changes (methylated A will pair with G)
27
what is the quality control mechanism for replication
polymerase - detects if DNA polymerase has inserted the wrong base uses a three to five prime exonuclease (enzyme that removes nucleotides) to remove wrong base and replace it with correct one =miss match repair
28
what is a nick in a DNA strand
a discontinuity in a double stranded DNA molecule where there is no phosphodiester bond between adjacent nucleotides usually due to damage or enzyme action
29
what do nicks in dna allow for
the release of torsion in the strand during replication | allow allow for DNA replication in the mis match repair systems
30
what does the enzyme RPA do
prevents exonuclease action, protecting the DNA strand from being digested by exoneucleases
31
what does polymerase protect against
miss matched bases
32
what is base excision repair
removal of damaged bases by DNA gylocsylase to generate an abasic site, creating a nicked by AP endonuclease which removes the sugar phosphate via a 5' incision flap removed by dRP lysase= nucleotide gap gap filled by DNA polymerase beta, ligated by dna lihase 3
33
what is nucleotide excision repair
repairs dna damage e.g. pyrmidine dimer distored helix recongised by XPC protein helicase unwinds DNA around damage nucleases cut section of damaged strand 5 and 3 to damafe TFIIH induces helicases, forms complex, fragment excised then filled by DNA polymerase beta and ligase
34
in eukaryotes where is NER enhances
in transcribed regions (transcribed couples repair) | different from elsewhere in genome as DNA legion recognised by stalling transcription complex
35
what is non homologous end joining (NHEJ)
repair of double strand breaks, to prevent loss of information form DNA (if chromosomes discontinuous) works well in 'clean breaks' when broken ends help together, broken ends ligated back together regardless of sequence but error prone in 'dirty breaks' where nucleotides lost
36
what often causes double strand breaks
single strand breaks that have not been repaired by other mechanisms
37
what happens in NHEJ if there is a dirty break
ends processed by nucleases, kinases e.g. artemis which trim the ends removing nucleotides ends then filled with DNA polymerases making them competent for ligation despite this nucleotides at site of break may be lost= error prone pathway
38
what is alternative NHEJ | aka micro homology mediated end joining
dirty break with non ligatable ends DNA ends undergo resection to generate single strand DNA complemetary DNA sequences eventually revealed on the two broken ends and these are paired to stabilise the ends (microhomology) non complemtary flaps removed by endonucleases and ends ligated this results in short deletion in repaired DNA
39
when can non homologous end joining repair DNA breaks
in G1,S and G2 phases
40
what is homologous recombination
form of DNA repair that happens in replication phases S and G2 double strand break repair using its duplicated sister chromatid as a template strand exchange between homologous duplexes occurs to form heteroduplex DNA (double stranded DNA from different molecules) this region of pair can be extended by branch migration via newly synthesised DNA
41
what is more accurate NHEJ or homologous recombination
homologous recombo
42
how do stem cells reduce the amount of DNA damage
as dont divide that much, reducing their number of replications and potential mistakes if mistake in stem cell division then could be passed through whole cell lineage instead stem cell divide infrequently into trans replicative cells that are differentiated and divide a lot, but these have short lifespan so not as bad if replicative error
43
what needs to happens in order to acquire altered cell functions (hallmark of cancer)
acquire a mutated phenotype | to do this need lots of DNA damage= genome instability
44
is DNA damage present in a pre cancerous cell
yes to make a cell precancerous need the activation of an oncogene/ inactivation of a tumour suppressor initiating DNA damage
45
what do ATM and ATR do
important kinases that are DNA damage signalling proteins | worls with 53BP1 ( a DNA repair protein) to create a DNA checkpoint
46
what are the steps in progression to cancer
oncogene activation -> pre cancerous cells (hyperplasia) loss of tumour suppressor function -> neoplasia (dysplasia) altered cell functions -> malignancy/ mets
47
what is neoplasia
tissue composed of cells with the ability to grow beyond their normal confines
48
what are the levels of DNA damage (oncurring and precious) like in pre cancerous cells
elevated = will have activated DNA repair and apoptosis
49
what happens to make a tissue convert to dysplasia
DNA damage and repair is occurring, as in pre cancerous cells, but apoptosis is not happening at the same rate
50
what happens to checkpoints in cancer
Pre cancerous cells and cancerous cells show signs of DNA damage also not exposed to external DNA damage. This activates checkpoint, but as the cancer develops the checkpoints seemed to have less effect (less cell death)
51
what inactivates check points in cancer
mutations in p53 or other checkpoint proteins e.g. ATM or chk2
52
what allows the transformation to cancrer
the loss of apoptotic/ senescent tumorigenesis barrier due to DNA damage once this happens cell growth and clonal expansion are uncontrolled
53
what mediated the tumorigenesis barrier
the DNA damage checkpoint | key protein of this is p53 (also ATM and Chek2)
54
does p53 prevent DNA damage
no, but works at checkpoint to prevent the damage causing any harm
55
how do oncogenes cause DNA damage
pre cancerous cells have expression of at least 1 oncogene this allows cell to proliferate due to growth promoting oncogene this causes replicative DNA damage and activates DNA damage repair increased transcription= faulty DNA synthesis (collapsed replication fork, truncated replications) this stimulates error prone DNA repair
56
why is oncogene driven transcription faulty
Expression of an oncogene gets elevated global transcription= premature S phase entry = replication stress. these increased transcriptions conflict with normal replication causing DNA and RNA encounters (from intergenic and intragenic firing origins) = fork collapse + genomic instability replication begins in different places that in normally does- intragenic origin firing= RNA and DNA collisions= truncated replications If there is a block to replication it can stall/ holt and cause e.g. truncations (collapsed transcription forks). This creates single stranded regions of DNA that are susceptible to further damage by e.g. free radicals. DNA breaks are one ended and cell doesn’t like this so joins to it another break elsewhere- translocation also limited RNA polymerase and transcription proteins due to increased transcription leaves transcripted RNA free. can bind with DNA from which is was transcribed creating hybrid R loop = trapped RNA polymerase = more polymerase collisions oncogene expression = (increased transcription -> R loop formation) + (shortened G1 phase -> increased intragenic origin firing) = increased replication stress (transcription - replication collisions) = tumorgenesis + genomic instability
57
what is a marker of replicative stress
phosphorylation of checkpoints
58
what stage does replication normally start and how is this different in cancer
in G1, fired by intergenic origins in cancer G1 is shorter, causing the firing of new replication origins intragenic as enter S phase prematurely this causes replication and transcription collisions
59
why are R loops so bad
reap RNA polymerase in transcribed region which makes more collisions with DNA polyermase= collapsed forks = repaired by NHEJ = translocations

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