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Medical Biochemistry > DNA Structure, Replication, and Repair > Flashcards

DNA Structure, Replication, and Repair Flashcards

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USMLE® Step 1 flashcards
1
Q

Nucleoside Analogs

A

Used in anti-viral and anti-cancer therapy
How do they work?
- analog is incorporated in the DNA during replication
- blocks further DNA synthesis (because it is missing an OH group)
- does not significantly affect host cell metabolism

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2
Q

Acyclovir

A

HSV deoxyguanosine analog (missing OH)

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3
Q

Azidothymidine (AZT)

A

HIV deoxythymidine analog (N3 instead of OH)

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4
Q

Nucleotide Polymerization Bond

A

3’,5’-phosophdiester bond

  • between 3’ OH and the 5’ P on the next sugar
  • results in chain POLARITY: free 5’-P and free 3’-OH
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5
Q

Nucleases

A

hydrolyze phosphodiester bonds

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6
Q

Exonucleases

A

cut at the end of a polynucleotide chain

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7
Q

Endonucleases

A

cleave internal phosphodiester bonds

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8
Q

Restriction Enzymes

A

site-specific cleavage

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9
Q

Secondary Structure Form of DNA

A

B-form (right handed double helix)

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10
Q

How many base pairs per helical turn?

A

10

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11
Q

Negative Supercoils

A

DNA double helix with FEWER HELICAL TURNS than the relaxed B-form DNA double helix

  • allow for compaction of DNA
  • facilitate DNA strand separation for DNA replication. transcription, and repair
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12
Q

DNA Topoisomerases

A

cut & paste to repair supercoiling form during replication

  • change and relax DNA
  • **important in order to remove POSITIVE SUPERCOILS AHEAD of the strand opening and “EXCESS” NEGATIVE SUPERCOILS BEHIND
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13
Q

DNA Topoisomerase Enzyme Activities

A

Nuclease and Ligase activities

  • transiently break one or both DNA strands
  • pass strands through the break
  • rejoin strands
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14
Q

Topo I

A

cuts a single strand of the helix

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15
Q

Topo II

A

cuts both strands of the helix

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16
Q

DNA Gyrase

A

ONLY FOUND IN PROKARYOTES
Topo II
- removes + and - supercoils

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17
Q

Antibacterial Topoisomerase Inhibitors

A

block activity of bacterial DNA gyrase

  • inhibit bacterial DNA synthesis
  • safe because NO DNA GYRASE in eukaryotic cells
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18
Q

Quinolones

A

Antibacterial Topoisomerase Inhibitor

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19
Q

Anti-Cancer Topoisomerase Inhibitor Therapy

A

target eukaryotic topoisomerases

  • inhibit ability of topoisomerases to join DNA
  • convert topoisomerases into DNA break agents
  • lead to cell death
  • SIDE EFFECTS ASSOCIATED because no way to differentiate which topos it is attacking
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20
Q

Chromatin Structure

A

DNA associated with HISTONE proteins

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21
Q

Histones

A

small basic proteins (rich in Arg and Lys)

  • five classes of histones
  • arranged in repeating units called nucleosomes
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22
Q

Five Classes of Histones

A

H1, H2A, H2B, H3, H4

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23
Q

Nucleosome core

A

DNA double helix supercoils around a histone octamer

  • two molecules of H2A, H2B, H3, H4 (not H1)
  • +/- charge interactions
  • H1 acts as spacer between nucleosome cores
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24
Q

DNA Spacer

A

histone H1 acts as spacer between nucleosome cores

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25
Q

Chromatin Condensation

A

H1 binds spacer DNA, promotes tight packing of nucleosomes

- chromatin winds into helical tubular coil

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26
Q

Solenoid

A

helical tubular coil of chromatin

- makes really large loops

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27
Q

Eukaryotic Chromosome Compaction

A

during Mitosis or Meiosis

  • solenoid winds upon itself to form very large DNA loops
  • DNA loops coil around a protein scaffold
  • DNA loops radiate from scaffold
  • CONDENSED METAPHASE CHROMOSOME FORMED (classic 4 arm structure with 2 chromatids joined by a centromere)
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28
Q

Condensed Metaphase Chromosome

A

classic 4-arm structure with 2 chromatids joined by a centromere

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29
Q

Replication mechanism in prokaryotes

A
  • Initiation at origin
  • DNA strand separation
  • RNA primers
  • DNA synthesis
  • Chain elongation
  • Proofreading
  • RNA primer excision
  • DNA ligation
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30
Q

What phase does replication take place during

A

S (synthesis) phase of the cell cycle

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31
Q

Prokaryote Origin

A
  • single OfR

- rich in A:T base pairs

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32
Q

DNA helicase

A

catalyzes DNA strand separation

  • binds near replication forks
  • uses ATP to break the H bonds between DNA strands
33
Q

Single Stranded Binding Proteins (SSBPs)

A

bind cooperatively

  • keep DNA strands apart
  • protects DNA from nucleases
34
Q

Inhibitors of Herpes Simplex Virus (HSV) Helicase

A

makes zipper stuck so DNA can’t replicate

  • stabilize interaction of helicase with viral DNA substrate
  • inhibit progression on DNA replication
  • effective against HSV strains resistant to nucleoside-based therapy
35
Q

Primase directionality

A

ALWAYS 5’->3’

36
Q

RNA primers

A
  • needed to INITIATE DNA synthesis
  • DNA polymerase cannot initiate on a single strand
  • provide a free 3’-OH as the acceptor for the first deoxyribonucleotide
37
Q

DNA synthesis is DISCONTINUOUS because:

A

DNA POLYMERASES CAN ONLY SYNTHESIZE DNA IN THE 5’->3’ DIRECTION

  • leading strand synthesized continuous
  • lagging strand discontinuous with OKAZAKI fragments
38
Q

DNA Polymerase III

A
  • primary replication polymerase in Prokaryotes

- has proofreading

39
Q

Chain elongation

A
  • catalyzed by DNA POLY III
  • nucleophilic attack of 3’OH of growing chain and 5’P of incoming deoxyribonucleotide triphosphate
  • formation of PHOSPHODIESTER bond
40
Q

DNA Polymerase III Proofreading

A

3’->5’ exonuclease activity to remove nucleotides introduced in error

41
Q

POST DNA Replication Proofreading

A

MMR Pathway

42
Q

Remdesivir

A 
Adenosine analog (SARS-coV2)
- modified sugar groups prevent further DNA chain elongation and block DNA synthesis
43
Q

DNA Polymerase I Proofreading

A

5’->3’ Exonuclease activity
- USED TO REMOVE RNA PRIMERS FROM OKAZAKI FRAGMENTS
(DNA then synthesized by DNA Poly I 5’->3’ Polymerase activity)

44
Q

RNA Primer Excision and DNA Ligation

A
  • DNA Poly III Synthesizes until blocked by RNA primer
  • DNA POLY I removes RNA Primer and finishes replication
  • DNA Ligase then joins Okazaki Fragments
45
Q

Major differences between prokaryotic and eukaryotic replication

A
  • Eukaryotic DNA has MANY origins

- Eukaryotic DNA has many more and different polymerases and proteins involved

46
Q

Pol Alpha

A

PREP

  • Eukaryotes
  • primer synthesis for both LEADING and LAGGING strands
  • PRIMASE activity synthesizes short stretches of RNA
  • DNA POLYMERASE activity then extends RNA primers with DNA
  • NO PROOFREADING
47
Q

Pol Delta

A

LAGGING; removes RNA primers and strand is completed

  • Eukaryotes
  • SYNTHESIZES the bulk of the LAGGING STRAND DNA
  • has PROOFREADING 3’->5’ EXONUCLEASE activity
48
Q

Exonuclease FEN1

A

degrades 5’ primer ends

49
Q

Pol Epsilon

A

LEADING (E lEading)

  • SYNTHESIZES bulk of LEADING STRAND DNA
  • has PROOFREADING 3’->5’ EXONUCLEASE activity
50
Q

Processivity factor PCNA

A

associates with POL delta and epsilon

51
Q

Eukaryotic DNA is packaged in nucleosomes

A
  • DNA double helix is associated with histones (nuclosomes)
  • nucleosomes are displaced as replication fork advances
  • histones remain loosely associated with parental strand
  • new histones synthesized simultaneous with DNA replication
  • nucleosomes reform behind the advancing replication fork
52
Q

Telomeres

A
  • ends of linear chromosomes
  • TAGGGGG telomeres it
  • can form telomeric loops (T-loops)
53
Q

Role of Telomeres

A

T-loops protect the ends of linear chromosomes from:
- recognition as broken DNA and degradation
- recombination
- end to end fusion
Prevent the loss of important coding sequences during replication

54
Q

Telomerase

A

ribonuleoprotein complex (RNA + protein)

  • has reverse transcriptase activity and makes DNA using RNA
  • synthesizes short DNA repeats extended chromosome with TAGGGG
55
Q

Telomerase is implicated in cell aging and cancer

A
  • telomerase active in ALL CELLS before birth; remains active in STEM CELLS AND GERM CELLS AFTER BIRTH
  • telomerase is INACTIVE in MOST SOMATIC cells AFTER birth (telomeres shorten with each cell division)
  • if shorten too far senescence occurs
  • IN HUMAN CANCERS telomerase is reactivated, and generally p53 activity is lost leading to unstable cell division and DNA elongation
56
Q

Senescence

A
  • occurs when telomere length declines to a critical point
  • DNA-damage sensors (p53) notice
  • induce cell growth arrest to prevent genomic instability
57
Q

Dyskeratosis congenita

A
  • inherited disease caused by REDUCED telomerase activity
  • defects seen most often in tissues in which CELLS DIVIDE RAPIDLY AND OFTEN
  • affects stem cells and germ cells
  • can cause mutation in RNA component of telomerase
    • patients generally die from bone marrow failure due to loss of hematopoietic renewal**
58
Q

DNA Repair Pathways

A
  • MMR
  • BER (base excision repair)
  • NER (global genomic nucleotide repair; transcription-coupled nucleotide excision repair)
  • Single-Strand Break Repair
  • Double-Strand Break Repair (non-homologous end joining; homologous recombination repair)
59
Q

MMR

A
  • Mismatched nucleotides; NO nucleotide damage
  • incorrect via substitution, deletion, or insertion
  • Recognize the mismatch and distinguish the newly synthesized strand from original
  • recognize via DNA methylation (Prok) or Okazaki framents (Euk)
  • Endonuclease cleaves strand on either side of mismatch
  • Helicase and exonuclease remove error
  • DNA Pol III fills the gap, followed by DNA ligase
60
Q

Cancers from MMR

A 
Lynch Syndrome (CRC +)
- MSH2 MLH1 mutations
61
Q

Base Excision Repair Pathway

A

DAMAGED BASE (caused by REACTIVE OXYGEN SPECIES; oxidation, deamination, depurination, alkylation, etc) occurs ~20,000x/day

  • GLYCOSYLASE recognizes damaged base and cleaves N-glycosidic bond between base and deoxyribose (specific glycosylase/base)
  • apurinic/apyrimidic ENDONUCLEASE cleaves sugar-phophate backbone
  • deoxyribose phosphate LYASE removes sugar-phosphate residue
  • DNA Pol I fills the gap, followed by DNA Ligase
  • ** NEEDS 3’OH to connect and replace, which is why the sugar backbone is removed as well! ***
62
Q

Defects in BER

A

mutation in gene encoding DNA glycosylase MYH leads to v high risk of CRC

63
Q

UV Dimer formation

A

UV induces formation of dimers between adjacent pyrimidines in DNA of skin cells

  • significant distortion of DNA helix
  • causes DNA frameshifts
  • without repair can result in skin cancer
  • ** Lesions corrected by NER! **
64
Q

ONLY way to extend DNA backbone and add a base

A

via BASE AND SUGAR BACKBONE

NEED free 3’OH for nucleotide attach between 3’OH and 5’ P

65
Q

Cigarette Smoke Carcinogens

A

Once oxidized covalently bind to G residues in the DNA of lung cells

  • interrupts normal H bonding, distorting the helix
  • causes DNA framshifts
  • without repair leads to lung cancer
    • Lesions corrected by NER! ***
66
Q

Nucleotide Excision Repair Pathways

A

BULKY FIX!
- can remove an INFINITE NUMBER OF LESIONS
- ONLY MECHANISM THAT REMOVES BULKY DNA ERRORS
2 Pathways
- Global Genomic NER (transcriptionally INACTIVE region of DNA)
- Transcription-coupled NER (transcriptionally ACTIVE region of DNA)

67
Q 
MMR
BER
NER (GG-NER; TC-NER)
SSBR
DSBR (NHEJ, HR)
A

MMR: wrong but not damaged
BER: single base damaged; need to remove sugar backbone to replace
NER: ONLY mechanism for multiple BULKY fix
- GG-NER: transcriptionally inactive; big cancer risk
- TC-NER: transcriptionally active; neuro disorder risk
SSBR: single missing nucleotide with frayed ends; ends processed by APTX
DSBR: Major NHEJ; Minor HR
- NHEJ: sloppy but gets the job done; occurs whenever
- HR: ONLY S and G2; PERFECT REPAIR; BRCAs/RADs

68
Q

Global Genomic NER (GG-NER)

A

Transcriptionally INACTIVE region of DNA
- recognize issue of helix distortion
- ENDONUCLEASES separate on both sides of problem
- HELICASE unwinds DNA to release damaged oligmer
- DNA POL I (d/E) fills gap
- DNA Ligase seals
CANCER RISK

69
Q

Xeroderma pigmenosum (XP)

A

Heriditary disorder from defects in GG-NER

  • patients show extreme solar sensitivity
  • highly increased risk of skin cancer and internal cancers
  • MIGHT also show progressive neuronal degeneration depending on WHICH XP PROTEIN IS AFFECTED
70
Q

Transcription Coupled NER (TC-NER)

A

Transcriptionally ACTIVE region of DNA
(DNA damage-induced helix disortion blocks progression of RNA pol II along template and halts gene transcription)
- proteins recognize stall of transcription
- RNA pol II displaced from lesion site
- recruitment of NER proteins
- HELICASE unwinds DNA to create a “bubble”
- EXCINUCLEASES make incisions on either side of lesion
- damaged oligomer is released
- DNA Pol I (d/E) fills gap
- DNA LIGASE seals chanin
- once repair is complete TRANSCRIPTION CAN RESUME
NEURO DISORDER RISK

71
Q

Cockayne Syndrome

A
  • hereditary developmental and neurological disorder associated with defects in TC-NER
  • mutations affect recognition of stalled RNA pol II
    Results in:
  • growth and mental retardation
  • neurological deficiencies
  • sun sensitivity
    *** DO NOT have INCREASED CANCER RISK vs. XP
  • because transcription does not resume after RNA pol II is blocked
  • damaged transcriptionally active cells likely under cell death via apoptosis
    (cell dies rather than being transcribed so do not have the chance to proliferate)
72
Q

Single-strand Break Repair Pathway causes

A
  • breaks in one strand of the DNA double helix; commonly caused by reactive O2 species, BER issues, and TOPO I without resealance
  • usually associated with loss of single nucleotide and damaged temini
73
Q

SSB Repair Mechanism

A
  • SSB recognized
  • Recruits XRCC1 which recruits multiple repair proteins
  • APTX processes the broken ends restoring proper 3’OH or 5’P groups
  • DNA polB can insert missing nucleotide
  • DNA ligation
74
Q

Ataxia Oculomotor Apraxia (AOA1)

A
  • autosomal uncoordinated eye movement disorder

- caused by mutation in the APRATAXIN gene (APTX) (DNA end processor)

75
Q

Double-Strand Break Repair Pathway

A
  • can be caused by a lot of stuff
  • can severely compromise genome stability; lead to loss of chromosome fragments in mitosis; cause cancer due to joining of wrong ends; lead to chromosome translocations
    2 repair pathways
  • Non-homologous end joining (NHEJ)
  • Homologous recombination Repair (HR)
76
Q

Non-homologous Endo Joining (NHEJ)

A

MAJOR DSB repair pathway
- can occur whenver
- ERROR Prone! rejoins random ends, HOWEVER repairs structural integrity so leads to some loss but not overwhelming loss
- KU70/KU80 sense and bind DNA broken end
- Artemis recruited and remove bad ends
DNA ligase rejoins ends

77
Q

Homologous Recombination Repair

A

RESTRICTED to S and G2 PHASES (needs sister chromatid)
- undamaged homologous strand serves as template to transfer genetic information and repair broken DNA
NON MUTAGENIC
- RAD52 binds DNA ends
- RAD51 recombinase searches for SEQUENCE HOMOLOGY
** Human BRCA1 and BRCA2 regulate RAD 51 **
- NUCLEASE and HELICASE acitivites are involved, followed by joining of the strands
NO CHANGE IN DNA SEQUENCE

78
Q

BRCA1 & BRCA2

A

Breast Cancer Susceptibility Genes
- Mutation in BRCA affects DSB HR
- tumors in BRCA carriers are more sensitive to ionizing radiation because of issues with DSB HR repair
Anti-cancer drugs which induce DSBs good chemotherapy options
- severe damage=cell death

79
Q

Ataxia telangiectasia (AT)

A
  • autosomal recessive disorder
  • hypersensitivity to ionizing radiation
  • associated with mutation in ATM protein which is activated by DSBs
  • slows cell cycle to allow repair but increases chance of improper joining and cancer

Medical Biochemistry (7 decks)

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