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Genotoxic stress Flashcards

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Biology 101 flashcards
1
Q

What is Genotoxic stress

A

Refers to the insult or deleterious effect or biological, chemical or physical agents on the hereditary material and releated genetic functions

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2
Q

What is involved in mutagenesis

A

Damage to cellular DNA and the development of cancer

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3
Q

Can genomic mutations be carried over into the daughter generations of cells

A

YES if the mutation is not repaired prior to mitosis

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4
Q

What are the three possible responses once cells lose their ability to repair damaged DNA

A

Senescent (irreversibly dormant), apoptotic, or maligant

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5
Q

What are examples of exogenous genotoxic agents

A

Chemical or physical nature such as chemical mutagens UV light or ionizing radiation

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6
Q

What are examples of endogenous factors

A

Regular products of cellular metabolism ROS and ordinary errors in DNA replication

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7
Q

What are modfications of indvidual nucleotides

A

Demination, depurination, oxidation, alkylation

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8
Q

What is exogenous DNA damage usually associated with

A

Bulky lesions and ss/ds

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9
Q

What is the phosphate group linked by

A

Phosphoester bond to a pentose sugar which is then linked to a N-glycosyl bond

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10
Q

What are the three sensitivie sites for DNA lesions

A

Amino group of adenine and cytosine
N-glycosyl bonds
Phosphodiester bonds

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11
Q

What is depurination and does it occur spontaneously for mismatch excision repair

A

Hydrolysis of N-glycosyl bond occurs spontaneously when the base is purine

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12
Q

What happens in depurnation

A

Releass guanine and adenine resulting in abasic/apurnic site

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13
Q

What is Demination

A

Spontaneous removal of an amino group from cytosine guanine and adenine which coverts it to uracil xanthine and hypoxanthine

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14
Q

What is 8-Oxoguanine

A

Oxidation of guanine where guanine normally pairs with cytosine 8-oxoguanine can also mis pair with adiene

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15
Q

What is the substitution called from 8-oxoguanine

A

CG to AT

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16
Q

What is the most common type of point mutation in humans

A

C to T which is caused by demination of 5-methyl-Cytosine

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17
Q

How are T-G mismatches always repaired

A

Removing the T and replacing it with aC which is called base excision repair

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18
Q

WHat does base excision repair take place

A

Prior to DNA replication

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19
Q

What are the four major steps of BER

A
  1. Recognition of damaged bases and T-G mismatches by DNA glycosylase which flips the base out of the helix and hydrolyzes the N-glycosidic bond leaving AP site
  2. DNA strand cut; AP endonuclease cuts the DNA backbone at the AP site
  3. Excision of the AP site; AP lyase which is associated with DNA polymerase B removes the dexoyribose-phosphate AP site making a gap within DNA strand
  4. Gap repair DNA polymerase B fills the fap and DNA ligase seals it
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19
Q

When is mismatch excision repair used

A

Base-pair mismatches and insertion or deletions of one or few nucleotides that are accidentally introduced by DNA polymerases during replication

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19
Q

What are glycosylases sensors to

A

Damaged bases and mismatches

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20
Q

What are the three steps of mismatch repair

A
  1. Recognition of mispaired segment of DNA by MSH2/MSH6 protien complex which distinguishes between the template and newly synthesized daughter strand
  2. Excision of DNA segment around the mismatch
  3. Gap repair DNA polymerase S fills the gap and DNA ligase connects the new section of DNA to the backbone
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21
Q

What are the three different types of DNA-modifying enzymes for Step 2

For mismatch excision repair

A

DNA endonuclease complex (MLH1 and PMS2) which cuts the newly synthesized daughter strand DNA helicase unwinds the helix and DNA exonuclease which removes the nucleotides from the cut ends including mismatched base

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22
Q

What is MSH2 and MSH6

A

A sensor

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23
Q

What is Lynch syndrome associated with

A

Mutant forms of protiens essential for mismatch exicsion repair

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24
Q

What is a predispostion of nonpolyposis colorectal cancer

A

Loss of function mutations of the sensor protien MSH2 and MLH1

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25
Q

What does alkylating agents do

A

Transfer carbo-containg methy and ethyl to N and O atoms in the bases which then particpate in hydrogen bonds in DNA double helixx

26
Q

What can the modfication of alkylating agents do

A

Innocuous cytotoxic or mutagenic

27
Q

What alkylation is harmless

A

N7 of guanine does not change the base=paring properites

28
Q

What alkylation causes harm

A

N3 of adenine is more serious because it creates a base that cannot base pair properly with any other base a non coding base DNA replication will then then stop and kill the cell and the base modification is cytotoxic

29
Q

What do mutagenic mutations result from

A

Alkylation of the nitrogen and oxygen atoms that are directly involved in base paring

30
Q

What is an example of a mutagenic mutation

A

Alkylation of the O6 guanine by EMS which transfers the ethyl group to DNA leads to the replacment of. G-C pair by A-T pair. O6 ethylguanine base pairs with T instead of cytoside

31
Q

What is EMS used

A

Common laboratory mutagen which is used to induce mutations in different types of cells

32
Q

What is mustard gas from

A

Alkylating agents have two recative sites which creat interstrand crosslinks due to cytoxic effects

33
Q

What is alkyltransferases

A

Capable of re-pairing DNA by damage reversal by removing methyl, ethyl and even larger alkyl groups

34
Q

How do alkyltransferase work

A

Single step reaction direct alkyl group molecule from DNA to a cysteine residue (sulfhydryl group) in the active center of the repair molecule. Alkyltransferase then becomes irreversibly inactivated and guanine is restoresed

35
Q

Where does the alkyltransferase remove alkyl groups from what positions

A

O6 from guanine and O4 poition of thymine

36
Q

What is alkyltransferases known as

A

Sucide enzyme because it is used up during the repair reaction

37
Q

Do all bases asborb UV light

A

YES

38
Q

What does UV damage do

A

Cross links adjacent pyrimidines on the same DNA strand

39
Q

What is the most common type of DNA damage and what is refered to as

A

Formation of thymine-thymine dimers connected by C-C bonds known as bulky lesions because the normal DNA shape is distoreted making DNA Kinks

40
Q

What does nucleotide excision repair fix

A

DNA regions containing chemically modified bases or bulky damage that distort the normal shape of DNA locally

41
Q

What are the four steps of NER

A
  1. Initial recognition of pyrimidine dimers by a XP-C 23B protien (thymine-thymine dimer)
  2. Opening of DNA double helix the XP-C/23B protein complex recruits transcription factor TFIIH the ATP-powered helixase starts to paritally unwind the double helix and then XP-G and RPA protien bind and further unwinf and stabilize the helix forming a buble
  3. Excision of DNA lesion segment; endonuclease XP-F and XP-G cut on the damaged strand at points 24-32 bases apart on each side the endonuclease then makes two DNA cuts which releases the DNA fragment with the damaged bases damaged DNA fragment is degraded to mono nucleotides
  4. Gap repair filled by DNA polymerase then sealed by DNA ligase
42
Q

Are exonuclease required to make the DNA gap

A

NO

43
Q

What is transcpriton couple NER

A

The mechanism operates slightly different in the regions of genome being activly transcrpited

44
Q

What is different about transcription-coupled NER and global

A

In recognition of DNA lesions they use RNA polymerase as a sensor then recurits CSB which then triggers the opening of the DNA helix and recruits RFIIH and other factors (step 2 and 4) ( doesn’t use XP-C/23B complex)

45
Q

What does Xeroderma pigemtosum name

A

Many proteins involved in NER mechanisms

46
Q

What disease does XP protiens cause

A

Rare autsomal recessive disorder of DNA reapiar that is characaterzied by sun sensitivity and UV radiation-induced skin and mucous membrane cancers 1000 more likely to develop skin cancer when exposed to the UV rays in sunlight mutated XP genes and NER cannot repair DNA damage induced by UV radiation

47
Q

What can gamma and X-rays do

A

Much more energetic than UV light and can ionize the molecules around DNA especially water and form highly reactive free radicals

48
Q

What can these radicals do that are caused by ionizing radiation

A

Attack DNA by altering bases and breaking strands

49
Q

How can single strands be repaired

A

BER
MER
NER

50
Q

What are the two ways to deal with dsDNA breaks

A

NHEJ
HR

51
Q

What does NHEJ involve

A

Direct ligation of two DSB little or no sequence homology required

52
Q

What is a key factor of NHEJ

A

Doesnt need a sister chromtid so it can occur during any phase of they cycle

53
Q

What are some downsides of NHEJ

A

Limited loss of genetic information resulting is short deletions ligation of the incorrect ends if multiple DSB are present generate large deletions or chromsomal rerrangments

54
Q

What does HR need

A

Template for repair which allows it to restore any missing genetic information largely accurate

55
Q

What is used at the repair remplate in HR

A

The sister chromatid

56
Q

What cell cylce can HR occur at

A

S G2

57
Q

What are the steps of NHEJ

A
  1. DNA end binding and bridging a complex of KU proteins and DNA dependent protein kinase binds to the ends of DSB KU hetrodimer forms a ring and enricles the duplex DNA that forms a brige or synapse between the broken end
  2. Terminal end processing KU hetrodimer and DNA-PK recruit and activate other proteins that are required for the processing of DNA ends including exonuclease that trim overhanging ends
  3. Ligation the blunt DNA ends are joined together by DNA ligase
58
Q

What is the KU heterodimer

A

KU70 and KU80

59
Q

What is the steps of HR

A
  1. DSB recognition: DSB sensors are poly(ADP) polymerase PARP and MRN complex which also mediate initial DSB resection
    2.Extensive DNA resection: this occurs with the help of several protiens including BRCA1 activation of all protiens is controlled by ATM (required to form overhanging 3’ ssDNA ends coated with RPA)
  2. Assembly of RAD51 filaments the overhanging 3’ ssDNA needs to be activated RPA displacement with RAD51 which is coordinated by BRCA2
  3. DNA invasion: RAD51 catalyzes invasion of 3’ ssDNA ends into homologous DNA of the homologues chromsome
  4. Hoilday junction formation and resolution Holiday junctions are branched DNA structure formed by strand exchange during recombination that provides DNA templates to repair DNA lesions. The repair strands seperate
60
Q

What is a sensor of DSB in NHEJ

A

KU hetro dimer

61
Q

What defects in DNA reapir by HR caused by

A

Inheritance of one mutant allele of the BRCA1 and BCRA2 genes results in predisposition to breast and ovarian cancer

62
Q

What does BRCA1 controal

A

Step of extensive DSB resection

63
Q

What does BRCA2 control

A

assembly of RAD51 filaments and invasion

Cell Bio (13 decks)

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