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CMCB Fall > DNA #17-20 part 2 > Flashcards

DNA #17-20 part 2 Flashcards

1
Q

What are the functions of DNA Topoisomerases?

A

REVERSIBLY add themselves COVALENTLY to the DNA backbond, breaking the backbond phosphodietster bond so that it can releive the strain on the ds DNA ahead of the replication fork

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2
Q

What is Topoisomerase I and function?

A

Uses Tyrosine hydroxyl group to insert into the backbone, creating Tyr-O-Phosphate linkages; now strained DNA can rotate freely around remaining backbond

ONce strain releieved, reaction is reversed, re-creating phosphodietser bond in backbone

Step is reversible and no ATP is consumed

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3
Q

What is the function of topoisomerase II?

3 steps:

A

Untangles the DNA strands (since there are multiple 46 cm strands of dobule helix in a 10-20 um dimater

  1. creates ds break in one piece of DNA
  2. causes the intact double helix to pass through the break
  3. reseasl the break

Driven by ATP Hydrolysis

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4
Q

What are drug inhibitors of Topoisomerase I (2)

A

Irinotecan

Topotecan

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5
Q

What are drug inhibitors of Topoisiomearse II

A

Etoposide

Tenipososide

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6
Q

What antibiotics are inhibitors of PROKARYOTIC Topoisomearse II

A

Novobiocin

Nalidixic acid

Ciprofloxacin

selecftive inhibitors

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7
Q

AKA prok Topoisomerase II

A

DNA gyrase

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8
Q

What are the special repetitive sequences at teh ends of chromosomes?

A

Telomeres

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9
Q

What happens when replication reaches the end of a telomere?

What does this enzyme do?

A

repetiive sequences attract an enzyme called TELOMERASE, which brings along its own RNA template as a primer

Telomerase then adds multiple copies of the short repetitive sequence to the chromosome ends–> This serves ast eh template for DNA polymerase

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10
Q

How do telomeres solve another problelm?

A

ends of chorocomes could appear to cell as a DS DNA break that needs to be repaired

repetitive telomere sequences are recognized by the cell as true chromosoe ends

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11
Q

What is sickle cell anemia?

What is the result?

A

result of a single nucleotide mutation in the Beta Globin gene

Result” very water-solutble glutamate on the surface of the protein is changed to valline

Glutamate (-)–> Valine (h-phobic)

Causes multible Hgb moleucles to adhere to each otehr in insoluble fibrous precipitates that can deforme the RBCs adn make them fragile

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12
Q

What is the error rate for DNA polymerase? for mistmatch repair mechanisms?

A

DNA polymerase 1/10,000,000

Mismatch repair mechanisms fix 99% of errors

overall is 1/1,000,000,000

avg is 6 bp/replication

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13
Q

Mismatch (replication) eros, what are two remedies?

A
  1. DNA poly has a proofreading activity,

2. There is a strand-directed mismatch repair system, making use of MutS and MutL proteins

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14
Q

What causes Post-replication mismatch?

What happens t them moleculalry?

A

Chemical, UV, or radiation-induced damage

Common problems are depurination, deamination, and thymine dimerization

or ds breaks

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15
Q

In newly synthesized DNA, mismatches that escape proofreading are detected by which protein (prok? euk?)

A

MutS (Pro) or MSH2 (euk)

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16
Q

What is a mismatch?

A

cuases some mismatch in the double helix conformation

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17
Q

How does mismatch repair machinery knwo which strand is the correct one?

A

newly synthesized strand has a numbe ro fnicks (backbone breas), makring it as the one in need of repair. NIcks only stay for short time after replication fork passes, so repair system must happen very quickly

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18
Q

When MutS detects a problem what protein associates it with to scan the DNA for the nick ? in pro and euk

A

in prokarytoes, MutL ass. wth MutS and scans along DNA until nick. A NUCLEASE is then recurited and it cleaves nucleotides off the newly synthesized strang back to MutS

DNA Polymerase rebuils new strand, and LIGASE completes repair

MLH1 or MLH3 in Euk

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19
Q

How can DNA be damaged?

A

Thermal Collisions with other molecules, encounter with chemically reactive metabolic intermediates or xenobiotics, or exposure with chemically reactive metabolic intermediates or xenobiotics, or exposure to high energy radiation (UV or Xrays)

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20
Q

What is depurination and its consequences

A

(loss of one of the purine bases)

This leaves the backbone intact, but there is a free hydroxyl group on teh 1 position of deoxyribose

This can lead to loss of nucleotide pair (shortenng of gene by one base, and casuing a frameshift in converting DNA code to protein sequence)

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21
Q

What is deamination and its consequences

A

loss of amino roup

COnverts cytosine to uracil –> can tlead to CG pair to an AT pair

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22
Q

UV radiation can lead to?

A

thymines to become covalently attached

results in Thymine Dimer–> stall DNA replication machinery inhigbitn cell replication

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23
Q

Other pyrimidine dimers (T-C and C-C) are possible but less common

A

yep

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24
Q

What are two main pathways for repairing these kinds of damage?

A

Base excision repair

nucleotide exicision repair

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25
Q

What is the most common kind of chemical damage?

A

Depurination

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26
Q

What does Base Excision Repair take care of?

A

Deamination

Depurination

Some kinds of oxidative damage to DNA

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27
Q

What initiates Base Excision Repair?

A

Initiated by family of DNA glycosylase enzymes that scan along the DNA “flipping out” one base at a time and examining it

when damaged base is recognized, its GLYCOSYL linkage is borken

Now missing tooth is recognized by ENDONUCCLEASE –>deoxyribose phosphate removed –> DNA polymerase addes new nucleotide –> DNA LIGASE seals nick

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28
Q

What is nucleotide Excision Repair?

A

When larger structural damage takes place –> nucletodie excision repair comes to rescue

Pyrimidne Dimer CT
or Polycyclic aromatic H-carbons which are known carcinogens

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29
Q

Process of Nucleotide Excision Repair

A

multienzyme complex scans DNA for large distortions in double helix

When it encoutners such a situation, cleaves phosphodiester backbone on both sides of the lesion

DNA helicase removes the damaged strand

Repairs are carreid out with DNA polymearsa nd DNA ligase

30
Q

what enzyme removes a damaged strand in Nucleotide Excision Repair?

A

DNA Helicase

31
Q

Summary of Repairing DNA Damage (3 enzymes

A
  1. Recognize and excise –NUCLEASE
  2. Resynthesize- DNA Polymerase
  3. Reconnect backbone —LIGASE
32
Q

What disease ffrom defects in repair of thymine dimers ?

A

Xeroderma Pigmentosum

affected inviducals are highly susceptible to basal cell carcinoma and other skin malignancies

33
Q

What is the most common rmechanism for repairing double stranded beaks in somatic cells?

A

nonhomologous end-joining

ds breaks are very dangerous

34
Q

How does non-homologous end joining work?

A

Enzyme complex brings the ends together and joins them with a ligase, although some bp may be lost in the process

This is a quick and dirty fix! ,

Net resulg: ds break repaired, with deletion of nucleotides at the repair site

35
Q

What if ds damage is in a critical spot?

A

it is likely that it will be signaled for apoptosis

36
Q

What is homologous recombinatino?

A

More conservative way to repair the break, ensuring that no base pair is lost

makes use of the “backup” copy that is the toehr copy of the chrosomeome

37
Q

Proces of homologous recombination

A

broken DNA must locate a highly homolgous ds DNA (not necessarily identical)

  1. nuclease needs to process broken ends sot hat tehre is a stretch of ss DNA on each
  2. Loose ends must FIND highly homolous ds DNA on teh other copy. ds DNA dissociaets enough for single strand to move in and pair up –> forming Holliday junction
  3. Invading strand is extended by repair DNA Polymerase
  4. Ligase links the backbone break, completing repiar without any loss of nuceotides

Homologus recominbation occurs most offten very soon after a short stretch of NDA has been replciated ; before packaged into chromatin

38
Q

What the branch point that is established in homologus recombination called?

A

Holliday Junction

39
Q

What extends the invading strand?

A

repair DNA plymerase

40
Q

What is homologous recobination and its process?

A
  1. Nucleasuse trims loose ends ot produce streteches of ss DNA

Branch points form with intact partner –> HOLLIDAY JUNCITONS

  1. set of recombination proteins stabilize junctions (helicase powered by ATP hydroylsis) that can cause branch point to migrate along the chain, effectively increaing the size of DNA segment being swapped
  2. Holliday junciton is RESOLVED, by inducing ss cuts then connecting loose ends witha ligase
41
Q

What is gene conversion?

A

during misosi, half of the genes parceled out should be maternal and half paternal, but on rare occasions, it is possible for this law to be “bypassed”

Thisis gne coversion, that it apears that one copy of a gene is coverted to the other copy

42
Q

How can gene conversions happen?

A
  1. During homologous recombination processs

tumor suppressor protein, that was itially heterozygours, with one good copy and one mutated copy. If copiees utated copy ont both strands, then adverse

  1. durin MISMATCH repair for slight mismatches foloowing homolgous recobination (X chromosome )

either strand can be emplate, the other strand is converted to the other allele

43
Q

What are Trasnposable Elements

A

“jumping genes”

short, specialized segments of DNA that contain informatino necessary for themt o insert themselves virtually anywhere in the genome

In eukaryotes, typically can’t leave the cell, so effects are limited to cellt hey reside in and its progeny

IN bacteria, these mobile elemetns serve to transmit antibiotic resistance from one cell to another

44
Q

What is the function of transposase gene?

A

has the enzymatic activ ity necessary to carry out insertino of the whole segment into a new location

45
Q

What is the fucntion of the DNA recognition sequence

A

located on each end of the tranposon

they are recognized by the transposase as teh boundearies of DNA to be moved

IN bacteria, these mobile elemetns serve to transmit antibiotic resistance from one cell to another

46
Q

What mechanisms are used to transfer DNA transposons?

A
  1. cut and paste?

2. Replicative

47
Q

What are retrotransporsomes?

A

Unique to Euk!

Much larger group of transposabe elements

Info flows from RNA to DNA in one stge of with a reverse transcriptase

48
Q

What two groups are Retrotransposons?

A
  1. Long Terminal repeats (LTR) retrotranpsosons

LTR has shown no activity/little activity

  1. Non-LTR Retrotransposons

most activity seen is due to non-LTR retrotransposn - there are 3 major groups and many smaller groups

49
Q

What are three main groups of non-LTR Retrotransposons

A
  1. Long Interspersed Element 1 (LINE-1 or L1)
  2. Alu elements (named for a restriction enzyme)
  3. SVA elements
50
Q

What are L1 elements/

A

part of non-LTR Retrotrasnsposons

6,000 bp long
L1 elements contain two open reading frames (seqeunces that can be transcribed/translated to proteins)

ORF1 codes for an RNA binding protein

ORF2 codes for a protein with ENDONUCLEASE and REVERSE Transcriptase activiteis

start with RNA polymerase promotoer, so that RNA polymerase can make copies of entire L1 element

Activities enable L1 elements to copy themselves and re-insert copies to new locations in the genome

51
Q

How many L1 copies are the human genome?

A

~500,000 copies

most hae mutated over time and lost teh ability to move

52
Q

What are ALU sequences?

A

shorter (280 bp) and do not contain coding sequences

53
Q

What are SVA elements?

A

about 2,800 bp in lenght and also do not code for pretines

REly on L1 elemnts or other sources of revertse transcriptase in order to be copied and transposed;

There are over 1 millino copies of ALu and 3,000 copies of SVA in the human genome

54
Q

How can the different transposable elements lead to disease?

A

Transposon or retrotransposon can insert early in embryogenisis or can damage gene and lead to genetic disease;

inserts in DNA repair gene or tumor suppressor gene –> cancer cell line

  1. L1 promotor can up-regulate expression of a gene
  2. Alu promoter may cuase production of micro-RNA which can lea to suppression of affected gene
  3. some TE sequences can inroduce p5k3 binding sites, altering gene expression
  4. insertion of repeated sequences in opposite orientations can cause the resulting mRNA copy to form ds RNA, with consequences for RNA editing enyzmes

**TEs have potentia to distrupt genes, gene expression, and protein expression if they are inserted in the wrong places

2.

55
Q

How does DNA protect itself from transposable elements?

A

DNA meythylation!

Suppresses gene exptression

Some mRNA editing machinery (APOBECs) may also inhibit L1 and Alu retrotranposition

56
Q

What are vriuses?

A

mobile genetic elements tha tcan escape from cells and infect other cells. Theya re more than pieces of genetic info (RNA or DNA) with a protetive coat

57
Q

How do viruses carry genetic info

A

s DNA, ss DAN ,ss RNA

58
Q

What is a retrovirus

A

Use RNA from genome ,
use Reverse Transcriptase to make DNA copy then INTEGRASE to integrae the new DNA into host cell’s DNA

virus is not part of host cell in a LATENT form (called provirus)

59
Q

When is viral DNA expressed?

A

when host cell’s RNA polymerase makes RNA copies of the viral DNA, many factors can affect length of latency period

RNA copies have new copies of viral genome and mRAN coding for viral proteins

60
Q

What are virus specific proteins?

A

reverse transcripatse,
integrase,
and proteases sometimes

can be used as targets during drug development

Retverse transcriptase has NO PROOFREADING capability , many copies mutated

61
Q

What kindof drugs against RT

A

coctail that attacks three different enzymes

Usually protease inhibitors against resistant strains of HIV

62
Q

What is Xeroderma Pigmentosum

A

Genetically heterogenous autosomal recessive disorder characterized by incerased sensitivity to sunlight

development of carcinomas at an early age

some patienst develop neurologic symptims or a more severe clinical phenotype known as de Sanctis-Cacchione syndrom

63
Q

what is TRICHOTHIODYSTROPHY (TTD)

A

sulfur-deficient brittle hair

patients with trichothidystrophy have gbrittle hair and nails (b/c of reduced content of cystein-rich matrix proteins)

ichtyotic skin, and phsyical/mental retardation

half patients display photosensitivey, correlated with a nucleotide excision repair (NER) defect

64
Q

Cockayne Syndrome

A

abnormal and slow growth and development tha tbeocme evidnet within first few years after birth

Cachetctic dwarfism describes the outward appearance of afflicated individuals

Cutaneous photosensitivey, thin, dry hair, progeroid appearance, porgressive pigmentary retinopathy, sensoineural hearing loss, dental caries, and characteristic stance in the ambulatory patient

65
Q

What mutation cause Xeroderma Pigmentosum, Trichothiodystropy, Cockayne Syndrome

A

Caused by mutations in any of several enzymes that are involved in Nucleotide Excision Repair

66
Q

What syndromes are caused by mutatinos in DNA Helicases called the RECQ helicase

A
  1. Werner Syndrome
  2. Bloom Syndrome
  3. Rothmund-Thomas Syndrome
67
Q

What is Werner Syndrome

A

AKA adult progeria

foloowing puberty, patients age rapidly

Patients reveal a propensity to develop chromosomal abberrations, including translocations, inversions, and deltions

68
Q

What is Bloom Syndrome

A

Autosomal recessive disorder characterized by proportionate pre- and postnatal growth deficiency

sun deficiency, sun sensitive, telangiectatic, hypo and hyperpigmented skin, predisposition to malignancy, and chromosomal instabiliyt

69
Q

What is Rothmund-Thomson Syndrome

A

hereditary dermatosis characterized by atrophy, pigmentation, and telangiectasia and frequencly accopanied by juvenile cataract, saddle nose, congentical bone defects, distrubances of hair gowth, and hypogonadism

chromosome instability and increased cancer susceptibility are also observed

70
Q

What are BRCA1 and BRCA2?

A

specific genes assocaited with hereditary breast cancer

both have complex roles in cell growth regulation, but both are associated with repair of double strand breaks

BRCA2 has been assoicated with other cancers a well (ovarian, prostate, others)

71
Q

What are hereditary nonpolyposis Colorecteral Cancer?

A

assosciated with mutations in strand-directed mismathc repair system

Most cases of this disease are caused by mutations of MSH2 or MLH1

show proclivity to early onset, predoinant proximal location of coon cancer

CMCB Fall (17 decks)

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