Topic 6 Flashcards

1
Q

What is dna damage and how can it occur

A

Any modification of dna that changes its coding properties or normal function in transcription or translation

Can happen spontaneously, induced by exposure to environmental factors like chemicals or radiation, or during replication

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2
Q

What can dna damage lead to

Are most mutations harmful

A

Mutations and genetic instability

Yes

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3
Q

What can cause changes in genetic material

A

Gene mutation (can be spontaneous or induced by mutagens)

Recombination (causing chromosomal rearrangements)

Transposable elements

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4
Q

Give an example of how recombination can change genetic material

A

If the chromosomes aren’t aligned properly during recombination

In one strand a deletion of a fragment can happen and a duplication in the other

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5
Q

What can cause gene mutations

A

Replication errors

Chemical modifications

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6
Q

What are the mutations that are caused by replication errors

What is the result of replication errors

A

Point mutations

Frameshift mutations

Mismatching, deletion, insertion, causing the reading frame to be same or diff

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7
Q

What are point mutations

A

A change in a single nucleotide

Can cause missense (change in nucleotide made diff amino acid) or nonsense mutations (premature stop codon

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8
Q

What are frameshift mutations

A

The slippage of the dna pol on the template causes a deletion in the new strand

Slippage on the new strand causes an addition in the new strand

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9
Q

Guanine and adenine structure and numbering

A

Both two rings

Guanine has c=o at c6

Adenine has c-NH2 at c6

In the five c ring numbers 7,8,9

In the 6 c ring the c 6 then go clockwise backward

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10
Q

Cytosine, thymine, uracil structure and numbering

A

Single ring for all

Cytosine has c-NH2 on c 4

Thymine has c=o on c 4 and methyl on c 5

Uracil same and thymine but no methyl on c 5

Number from 1 opposite to c 4 going clockwise

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11
Q

Which atom of purine and pyrimidines form bind with the sugar

A

Purine: N9

Pyrimidine: N1

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12
Q

What is a tautomeric shift

A

The dominant keto (c=o) and amino (c-nh2)

Turn to enol (c-oh) and imino (c-nh

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13
Q

Which nucleotides can have enol forms

Which can have imino

A

Guanine thymine and uracil

Adenine cytosine

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14
Q

What can enol form of thymine base pair with

Say how it changes

A

Keto guanine

T:A then T:G

after replication C:G

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15
Q

What can enol form of guanine base pair with

Say how it changes

A

Keto thymine

G:C to G:T

After replication A:T

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16
Q

What can imino form of adenine base pair with

Say how it changes

A

Amino form of cytosine

A:T to A:C

After replication G:C

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17
Q

What can imino form of cytosine base pair with

Say how it changes

A

The amino form of adenine

C:G to C:A

After replication T:A

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18
Q

What is the result of anomalous base pairing due to tautomeric shifts

A

Base pair transitions or transversions

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19
Q

What is a transition mutation

Transversion

A

Purine pyrimidines to purine pyrimidines (ex. G:C turns to A:T)

Purine pyrimidines to pyrimidines purine (ex. G:C turns to C:G)

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20
Q

Point mutations can be categorized into

A

Translation or transversion mitations

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21
Q

What are the two steps that point mutations occur in

At what pint is it actually a mutation

A
  1. Incorrect nucleotide is inserted during replication
  2. The mismatched base is not repaired and gets replicated

In step 1 it’s just a lesion/mismatch

In step 2 it’s a mutation

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22
Q

What is the teg-1 gene

A

A gene that when mitated causes tumour enhancement and over proliferation of mitotic cells

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23
Q

What is the mutation in teg-1 (oz230)

What is the mitation called

A

The AAG changed to UAG at codon 53 (position 257) , this causes a premature stop codon

Since UAG, called amber

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24
Q

What is the mutation in teg-1 (oz189)

What is the mitation called

A

UGG to UGA at codon 142

UGA means opal

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25
What is the UAA stop codon labeled as
Ochre
26
What does K53X means
Lysine 53rd codon X means a stop codon
27
If I have codon 53 how many nucleotides it this But in reality it’s listed as higher (257) why?
153 in the processed sequence This accounts for the fact that there are introns in the genomic sequence (unprocessed sequence)
28
What are indels and how are they caused
Insertions or deletions Caused by bad recombination of dna or dna pol slippage during replication
29
What is a reading frame What changes the reading frame
A contiguous non overlapping 3 nucleotide codon in DNA or RNA (has no introns) Framshift mutations
30
What happens if an indel mutation affects a multiple of 3 base pairs
The reading frame of the gene is unchanged since since either only one amino acid is gone or added
31
What are trinucleotide repeat/expansion disorders Give an example
When expansion of repeats of CAG CGG GAA CTG cause hereditary disorders even though no frameshift happens Ex. CAG expansion in the gene encoding Huntington causes the Huntington chorea disorder
32
What is fragile X syndrome Who does it affect more What gene is it in What is the normal number of repeat , number that makes you a carrier and the disease number
The most common form of mental retardation and Affects men more than women Expansion of CGG repeats in the FMR1 gene (fragile x mental retardation) Normal is 6-54 Carrier is 55-200 Disease is 200-1000
33
What is bad about fragile X syndrome
The fact that the CGG repeats get more and more expanded across generations means the offspring get worse and worse symptoms
34
How can the trinucleotide repeat disease get diagnosed using PCR
They can measure the number of repeats by the amount of BP in the PCr product If 300 nucleotides there are 100 repeats
35
In chemical damage of dna what can cause this
Hydrolytic reaction with water to damage the nucleotides and phosphodiester backbone Electrophillic attack of the DNA backbone by alkylating agents Reaction with oxygen species like hydrogen peroxide, hydroxyl radicals Alteration of the dna structure by irradiation from sunlight, x ray or uv
36
All in all, chemical damage to dna can happen why
Dietary and environmental stressors
37
In hydrolytic damage of nucleotides what is there
Deamination Depurination Depyrimidination
38
What is deamination
Removal of a amine group on a nucleotide
39
What gets Deaminated and what does it turn into
CAG Cytosine turns to uracil Adenine to hypoxanthine Guanine to Xanthine 5-me-cytosine to thymine
40
After Deamination , what can xanthine and hypoxanthine pair with What does this mean
Cytosine When guanine gets deaminated to xanthine there isn’t a problem because it’s still pairing with C
41
What does uracil pair with
Adenine
42
When changing from A G to hypoxanthine or xanthine what changes
The amine becomes c=o and the n gets an h
43
Where would we see 5 methyl cytosine
In CpG islands
44
In hydrolytic damage How does depurination and de pyrimidation happen
The hydrolytic reaction cleaves the glycosidic bond between the base and the backbone sugar This makes an abasic site (Ap site)
45
How often does dpurination occur
Under physiological condition 5000 bases per cell per day
46
What can be the result of the ap site
The backbone is unstable When is becomes unstable the sugar is in the open form and vulnerable to a nucleophile attack This leads to cleavage/breakage of the backbone
47
What causes oxidative damage of nucleotides Give examples
Cellular metabolism like respiration can make reactive oxygen species (ROS) The ROS are OH radicals, O2 radicals, and h2o2
48
What can ROS do to which nucleotides What does each turn into
Oxidize T and G T turns to thymine glycol G turns to 8-oxoguanine
49
What does thymine glycol and 8-oxo-guanine look like
Thymine glycol has two OH 8-oxoguanine has two c=o
50
What do thymine glycol and 8-oxoguanine result in
Thymine glycol is bulky due to the two OH so it stall the dna pol during replication 8-oxoguanine pairs with adenine
51
What causes alkylating damage of nucleotides
Alkylation’s agents (ch3-) from cigar smoke and environmental pollution The agent acts as a nucleophile
52
What are the highly reactive sites of the nucleotides that can get alkylated
N3 of A O6 of G N7 of G
53
What’s a special case of methylation of a nucleotide
S- adenosylmethionind (SAM) , a methyl donor to adenine can turn adenine Into N6 methyladenine (m6A) This makes the modified adenine behave like rna
54
What causes Deamination
In food preservatives , the sodium nitrate naNO3 and bisulfite HSO3- and nitrous acid (HNO2) cause Deamination
55
How can bisulfite help in bisulfite sequencing in studying epigenetics
The unmethylated cytosine gets deaminated into uracil So after replication it goes from C:G to T:A But methylated stays the same This is how you can see which were methylated
56
What is special about guanine in terms of the modifications it can have
It’s can have alkylation Deamination and oxidation all at the same time on that one base
57
What is the cause of uv induced damage on dna What is the most common result
It can cause cyclobutane pyrimidines dimers (CPD) The most common result is thymine dimers
58
On which atoms can the thymine dimers form
Formed by one bond between the c6 of one thymine and c4 of the other (6-4) Called 6-4PPs Or two bond between the c5 and C6 of the two thymines (6-5)
59
What is the likelihood of dimer formation in UB induced damage
TT >> TC > CT > CC
60
What is the result of dimer formation due to uv light
Causes a kink in the DNA so DNA pol stalls and cant replicate
61
What is a diesease caused by TT dimer formation due to UV light
Skin cancer
62
Aside from forming dimers what can ionizing radiation also do
The high energy causes the radiolysis of water which makes ROS These ROS can cause base loss (AP sites), strand breaks And dna protein cross links (dna and transcription factors are cross linked which stops gene expression)
63
What are intercalating agents and what do they do
They are chemicals that mimic the base pairs and intercalate between them They cause the dna pol to skip that region of dna and make indel and frameshift mutations Also change the dna topology by stretching them
64
What are examples of intercalating agents
Proflavin, ethidium bromide
65
What is hydroxylation and the result
Adding a hydroxyl group to the amino of cytosine Makes hydroxylaminocytosine (HC) HC binds to adenine So C:G to T:A
66
What are the base analogs
5-bromouracil 2-amino purine
67
What is 5-bromouracil (5-BrU) What does the keto form pair with What does the enol form pair with
A thymine analog which exists in the keto and the enol form Keto form pairs with adenine (no effect since stil T:A) Enol pairs with G
68
What is 2-amino purine (2-AP)
An adenine analog When 2-AP is protonated at N1 it pairs with C
69
What are alkylating agents Where does alkylation most readily occur
They are thing that introduce alkyl groups Occurs most readily at nucleophillic centres of the nucleotides Prefer GC rich regions to attack N7 guanine O6 GUANINE N3 adenine
70
When an aplkylating agent alkylates a base, when does it have the most affect
After replication, that’s when it becomes a mutation and bases get mismatched Then through more replication the mutations can get amplified
71
What are alkylating agents examples
EMS EES MNNG Nitrosamine Nitrosourea (used to introduce mutations)
72
What can also get alkylated by ems
O6 of guanine O4 of thymine
73
When researchers use EMS to alkylate something what type of mutation it it and why is it helpful
It’s usually a substitution mutation (GC to AT) Can induce a mutation using EMS to the organism and observe the outcome of the phenotype of the organism then attribute the change in phenotype to the function of the gene
74
What naturally occurring agents can be used to introduce inter strand and dna protein cross linking
Uv, ionizing radiation, bifunctional alkylating agents (such as psoralens)
75
What is psoralen
A naturally occurring compund from plants that is highly sensitive to light When added to dna, you expose it to light, the psoralen gets activated Cross linking agent that cross links the pyrimidines bases between two strands, links Stops cell division
76
How can psoralen be used as a treatment
Since it stops cell division though making kinks It’s used in PUVA (psoralen uv a) treatment of skin problems like psoriasis eczema and vitiligo
77
What dna damaging agents can be used in chemotherapy
Alkylating agent Crosslinker like cisplatin (which is an alkylating agent)
78
What does cisplatin do in chemotherapy
It’s causes dna damage by adding alkyl groups to the bases Damages the mitochondrial dna (its own type of dna) This activates cyt c which triggers the apoptosis pathway which causes the cell to die This kills the cancer cells since they are more likely to take up cisplatin
79
What are the classes of repair mechanisms
Direct reversal of DNA damage
80
What are the classes of repair mechanisms
Direct reversal of dna damage Base excision repair Nucleotide excision repair
81
What is the direct reversal of DNA damage used for What is included in it
Small common damage The mismatch repair system Photoreactivation of pyrimidines dimers Removal of a methyl group (from alkylation) by methyl transferase
82
What is included in. Base excision repair BER
The nitrogenous base is removed, then repair happens Specific for one type of damage base
83
What is included in nucleotide excision repair
The nucleotides is/are removed, then repaired General to many types of damage and is used to repair a larger region
84
what organisms have MMR systems When can the MMR happen
It’s conserved in prokaryotes and eukaryotes It repairs simple dna lesions (so first Gen mismatch), so once the lesion is replicated it can’t repair
85
What is the limitation of MMR
Misinsertions and short indels can’t be repaired Only small changes
86
In every _____ nucleotide dna pol causes ___ mismatch But in ecoli how does the MMR help
Every 10^6 Cause 1 Is makes it so every 10^9 or 10^10 nucleotides has a mutation because MMR repairs it
87
What is the first step in MMR system in e.coli
If a mismatch by dna pol 111 happens There is a palindromic sequence in the ecoli strands : GATC The newly made strand gets recognized by DAM methylase DAM methylase methylated the adenine residue in the GATC sequence in the parent strand of the dna There is a split second where the daughter strand is not methylated (this is hemimethylation) This lets the repair enzymes distinguish the parent strand from the daughter strand
88
If muts is mutated what happens
You get lots of mutations in. Ecoli because it’s essential for the MMR system
89
What are steps 2-5 of the MMR system in ecoli
MutS forms a complex with mutL on the dna The MutS/L complex scans the dna bidirectionally to find the mismatch and forms a loop where the mismatch is Once they find the mismatch, the complex recruits MutH to cleave at the unmethylated GATC (on the daughter strand) Then MutS/L complex recruits UvrD (helicase II) to unwind the dna in the direction of the mismatch When unwound, the strand with the mutH cleavage is dangling and an exonuclease comes and chews off the end with the mismatch
90
In MMR, when cleavage of the daughter strand at the 3’ end of the hemimethylated site (on the parent strand) happens what exonuclease gets recruited
A 5-3 exonuclease (since the end of the nick is the 5’ end on the daughter strand) RecJ or exonuclease VII
91
In MMR, when cleavage of the daughter strand at the 5’ end of the hemimethylated site (on the parent strand) happens what exonuclease gets recruited
A 3-5’ exonuclease since the end of the nick is the 3’ end of the daughter strand Exonuclease 1 or exonuclease X
92
What is steps 6 and 7 of MMR system (after the exonuclease degrade the mismatch)
The single stranded gap in the daughter strand is coated with single stranded DNA binding protien (SSB) This lets dna pol III come in and fill in the proper sequence, and the nick is sealed by ligase
93
What is the MMR system like in eukaryotes
They have proteins that are homologous to MutS and MutL But They lack homologs to MutH and DAM methylase They dont use methylation to distinguish between parent and daughter strands
94
What are CPD photolyases What is the chain length Where are they found Where are they not found
An enzyme which catalyzes the monomerization of CPD dimers A single polypeptide chain of 454 to 614 amino acids Found in bacterial, archeal, and eukaryotic cells. Not found in placental mammals
95
What is the structure of CPD photo Lyase
Has two noncovalently bound chromophores These chromophores absorb sunlight , meaning it needs the sun to be active and pull apart the dimers
96
How does the E. coli has CPD photo Lyase actually use sunlight to pull apart the dimers
It binds FADH Also has MTHF or 8-HDF chromophores MTHF or 8-HDF absorbs light and transfer electrons from the light to FADH Then FADH cleave the cyclobutane ring (dimers)
97
What gene encodes the CPD photolyase What domains does it have What is its expression in wildtype cells
phr (photoreactivstion) gene Aplha helical domain, alpha beta domain, a secondary pocket (for FADH to bind) Low expression of phr
98
What happens if the phr gene is mutated
No CPD photolyase activity Sensitive to UV exposure (since cant repair the dimers) So dna replication stalls: grow slowly and have low viability
99
What domain of the photolyase can harness the sun energy
The alpha helix domain which has the MTHF region
100
What is the process of CPD photolyase direct reversal repair
The photolyase binds to the thymine dimer in the presence of light Once bound it flips the TT dimer into its active site pocket using the phosphate backbone as a hinge The MTHF absorbs a photon from light, then transfers the energy to FADH in the catalytic site The excited FADH transfers electrons to the dimer, splitting it into two T (pyrimidines) The electron returns to the flavin radical and forms FADH. The CPD photolyase enzyme leaves
101
What type of reversal mechanism is the CDP photolyase repair
One step
102
What is o6 methyl guanine What does it pair with What mutation does it cause So what need to happen
A guanine that has been alkylated at O6 T GC to AT transition mutations Before the lesion turns into a mutation is need the because fixed
103
How does direct reversal of O6 methylguanine happen What organisms is it in
The methyl group of o6 meG is transferred to a cysteine residue In the enzyme O6 meG dna methyl transferase This corrects the o6 me guanine to regular guanine All organisms
104
What happens to the methyltransferase enzyme after direct reversal of O6 me guanine
Since it has been modified by taking in the methyl, it degrades itself
105
What is included in excision repair
BER NER (repairs indels, more nucleotides)
106
More simple lesions can be repaired by
MMR BER direct reversal of dimers or o6me guanine
107
What does BER repair
Single damaged nucleotides SsDNA breaks
108
How is prokaryotic/bacterial BER done
The damaged base is recognized by DNA glycosylase DNA glycosylase hydrolyzes the N-beta-glycosyl bond (glycosidic bond) between the base and the agitate of the back bone This makes an AP site (a basic site) The ssDNA at the AP site is cleaved by AP endonuclease AP endonuclease (since inside the strand) cleaves the DNA backbone at the AP site and makes a nick and released the 3’ OH and 5’ DRP (deoxyribose phosphate)
109
In prokaryotic BER what happens after the AP endonuclease makes a nick
The segment of the DNA is removed and sealed by the nick translation activity of Pol I Then dna ligase seals the remaining nick
110
What is the nick translation activity of Pol I How can it be used to label the dna
The dna pol 1 has two activities Able to be an exonuclease to remove nucleotides (in this case 5-3 since 5’ end is floating up) Also adds nucleotide from the 5-3 end It’s a technique that use to label the dna fragment since the dntp that it adds during nick translation can be labelled Then when repairing these get added and the dna is labelled
111
The DNA glycosylase is _____ What does this mean
Conserved Meaning all organisms have some type of glycosylase for BER that recognize diff types of damage bases
112
If cytosine gets deaminated and turn to uracil What bacterial glycosylase will do BER on it
Uracil DNA glycosylase (UDG) It works only on dna since lesion that make uracil only happen on dna Not work on RNA
113
What are each of the human glycolsylases and what do they fix
UNG (uracil dna N glycosylase) : ssU, U:G, U:A TDG (thymine DNA glycosylase) MPG (methyl purine DNA glycosylase) OGG1 (8-oxoguanine-glycosylase): 8-oxo-G MYH (MutY homolog): A:G, A:8-oxoG NTH1 (endonuclease 3 homolog) T-glycol, C-glycol
114
What happens in eukaryotic BER
The first two step are the same But after the AP endonuclease makes the nick there is two pathways: Long patch repair Short patch repair
115
What is the eukaryotic BER long patch repair
the eukaryotic polymerase doesn’t have the 5-3 nick translation exonuclease activity So the 5’ DRP end peels up And flap endonuclease chops it off and fills in the gap Then ligase seals the nicks
116
What is the eukaryotic BER shirt patch repair
The polymerase beta only fills in the gap from the damaged nucleotide The ligase seals the nicks
117
Since the nitrogenous bases in BER are facing inward How can the DNA glycosylase recognize the damage and flip out the damaged base
It scans the minor grooves of the helix in search of kinks Kinks caused by the damaged base not matching perfectly with the other base When lesion is recognized the dna bends a bit then the base gets flipped out But the adjacent bases are not disrupted
118
What does NER repair
Bulky damaged bases Indels Generally big lesions
119
What how does nucleotide excision repair work in prokaryotes How many nucleotides is the gap
The UvrA and UvrB complex scans the DNA helix for damage When a lesion is encountered, UVRA leaves, UVRB melt the two dna strands UVRB recruits UVRC excinuclease (excision endonuclease) UVRC makes a 5’ and 3’ nick on either side of the damaged nucleotides (damage in between both ends of cut) This makes a 12-13 nt ssDNA gap UVRD helicase releases the 12-13 nt fragment by unwinding the dna DNA pol 1 and ligase fill and seal the gap
120
What is the biggest difference in NER
UVRC Making two cuts Helicase unwinds the helix to remove the entire fragment
121
How does NER happen in eukaryotes How long of a gap is there
XPC scans for and recognizes the lesion XPB AND XPD are recruited to the lesion and separate the DNA to make a ssDNA bubble After bubble, RPA binds to the bubble and positions XPF and XPG on either side of the lesion XPF and XPG are nucleases XPG cleaves on the 3’ side and XPF the 5’ side A larger 24-32 nt fragment is displaced The PCNA clamp recruits a DNA pol to fill in the gap which is then sealed by ligase
122
What is transcription coupled DNA repair (TCR)
When there is unrepaired dna damage and transcription is starting The damage is recognized by the RNA polymerase The rna pol stalls at the site of the lesion When stalled, the pol leaves and recruits the NER proteins
123
What region of DNA would have the most TCR repair
The regions that are most highly transcribed
124
Is the RNA pol proofreading ability as strong as dna pol proofreading?
No
125
What is xeroderma Pigmentosum (XP)
A autosomal recessive disease It has a defective NER system where uv damage can’t be repaired So the skin cells are very photosensitive Leading the early onset skin cancer
126
What causes unequal crossing over of chromosomes and what does it lead to
If the chromosomes are not aligned properly during recombination, there will be unequal crossing over This causes a duplication on one chromosome and deletion in the other Leading to loss or enhancement in the phenotype
127
What causes unequal crossing over of chromosomes and what does it lead to
If the chromosomes are not aligned properly during recombination, there will be unequal crossing over This causes a duplication on one chromosome and deletion in the other Leading to loss or enhancement in the phenotype
128
In a paracentric chromosme what is the long arm and what is the short arm called
Long is Q Short is P
129
What are balanced rearrangements and the types
Paracentric inversion Pericentric inversion
130
What is paracentric inversion What is the result
An inversion of genetic content in the chromosome(so before A BCD now A CBD) But the genetic content is the same so in the parent (carrier) there is no phenotype change But during recombination in the offspring, four types of gamete are made Balanced: ABCD, A CBD Inviable: ABCA (a repeat) with two centromeres or DBCD (d repeat) with no centromere
131
In para centric inversion what invisible chromosomes are made and what is the cause
Either acentric (none) or dicentric (2) chromosomes Lead to unstable chromosomes and unviable offspring
132
What happens in pericentric inversion
Crossing over of pericentric chromosomes causes unbalanced gametes to be made They make duplicated or deficient segments of the genes near the inverted segment (ABCA OR DBCD) So it can make four gametes with balanced, balanced, unbalanced, unbalanced chromosomes But still one centromere in each
133
What is DSBR (double stranded break repair) What is a backup to it
Double stranded break happens due to radiation, If not repaired cell will die Since diploid cells, homologous recombination with the other chromosome can repair the damaged DNA So an allele on the homologous chromosome can be used as a template to replace the sequence on the damaged chromsome
134
How does DSBR get fixed
The double stranded broken chromosme goes through a set of cleavage This cleavage makes 3’ overhangs The 3’ overhang invades into the template strand (the homologous chromosome) This lead to two outcomes: SDSA or DSBR
135
What is SDSA in DSBR
Synthesis dependent strand annealing The two homologous chromosme are separated and there is no crossing over event
136
What is DSBR in DSBR
Invasion happens and the dna gets repaired But either non crossover or crossover dna is formed
137
What is NHEJ (non homologous end joining) What is the problem
The homologous chromosme is not always there to act as a template KU70/80 binds at each end of the DNA the is broken Other proteins are recruited and the two ends are ligated together Since forcing the two ends together, if the breakage caused deletion of DNA that deletion would stay MUTATIONS STILL PERSIST
138
What is translesion DNA synthesis
The dna is replicating a damaged dna strand DNA pol stalls during replication due to a lesion at the replication fork The replisome complex dissociates from the DNA Another DNA pol belonging to the Y family is recruited
139
What happens in translesion DNA synthesis (TLS) when the Y family polymerase is recruited
This dna pol has doesn’t have proof reading ability so forgiving to dna damage They will continue the replication with the mutation The mismatch can be repaired later
140
What is the end result of TLS
The damage is still there in the dna But the cell doesn’t die since if it just stopped replicating it would have died Allows survival with the mutation rather than just dying