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MCP Unit 2 > DNA Repair and Replication > Flashcards

DNA Repair and Replication Flashcards

1
Q

DNA replication

A
  • duplication of hereditary material
  • semiconservative
  • occurs once in cell cycle
  • begins at replication origins
  • forks and replisome
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2
Q

DNA repair

A
  • correction of mistakes in the hereditary material
  • DNA damage vs. mutation
  • sources and types of DNA damage
  • DNA repair mech-BER, NER, MMR
  • clinical relevance of DNA repair defects
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3
Q

degrees of genome instabilities

A
  • base pair changes
  • small scale insertions, deletions, or inversions
  • large scale segmental duplications, translocations
  • large scale repeat expansion- fragile X, huntingtons
  • whole chromosome loss or gain- down, klinefelter’s syndrome (XXY), patau- trisomy 13, triple X
  • cancer genome contains all of above changes (oncogene induced DNA damage)
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4
Q

DNA replication

A
  • 5’-3’
  • semiconservative (M & S- heavy and light DNA half and half)
  • multiple ORCs-early and late
  • leading goes 5’-3’, lagging needs Okazaki fragments (100-200 bp)
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5
Q

helicase

A

unzips DNA to expose templates for H bonding interactions with newly synthesized complementary strands

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6
Q

RPA (ssDNA binding protein)

A

-prevents exposed DNA strands from re-annealing

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7
Q

primase

A

RNA polymerase, lays down RNA primer

-leading and lagging strand (single vs multiple)

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8
Q

DNA pol E

A
  • leading strand

- synthesizes DNA

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9
Q

DNA pol delta

A

-lagging strand

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10
Q

sliding clamp

A
  • PCNA

- keels DNA pol on template

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11
Q

clamp loader

A
  • RF-C

- keeps clamp on to keep pol on

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12
Q

RNAse

A

removes RNA primers

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13
Q

DNA ligase

A

closes gaps b/n Okazaki fragments

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14
Q

DNA pol and self-correcting

A
  • 5’-3’ is polymerizing
  • 3’-5’ is exonuclease
  • both on palm part of pol
  • 1 error per 10 million nucleotides
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15
Q

exonucleases

A

-chew in one direction- can be either

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16
Q

endonucleases

A

-cut like scissors within DNA- not involved in replication

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17
Q

error prevention

A
  • DNA mismatch repair
  • proteins scan newly replicated DNA for mismatches, removes is, and synthesizes a new strand
  • makes mistake 1 in 10^9
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18
Q

mismatch repair mistakes

A
  • seven genes encoding for mismatch repair proteins
  • predisposition for cancer- hereditary non-polyposis colin cancer
  • accumulate mutations rapidly
  • mutator phenotype
  • hMSH2 and hMLH1
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19
Q

error prone DNA pol

A
  • damaged template needs low fidelity polymerases
  • lesion avoidance vs translesion synthesis
  • see picture
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20
Q

DNA pol alpha

A

-primase

21
Q

DNA pol delta

A

3-5 exo

lagging

22
Q

DNA pol epsilon

A

-3’-5’ exo

leading

23
Q

family X and Y pols

A

-error prone

24
Q

replication stress response

A
  • forks vulnerable to DNA damage or nucleotide starvation
  • ckpts deal with stress
  • if they don’t work-ssDNA, reversed forks, ds breaks
25
Q

replication stress response 2

A
  • lesions activate ckpts that stabilize forks
  • fork restart mediated by proteins (originally found in homologous recombination repair of ds breaks)
  • DNA-PKcs, Ku, DNA ligase IV-XRCC4, Artemis, XLF and Metnase
  • signaling or DNA end joining?
  • cancer therapies create fork stress
  • see picture
  • revolves around stabilized fork
26
Q

Ataxia Telangiectasia

A
  • susceptible to lymphomas
  • ataxia (abnormalities of balance)
  • telangiectasias in skin and eyes
  • chromosome abberations
  • immune dysfunction
  • mutations in ATM, protein kinase important for replication stress respons and regulates p53- accumulations
27
Q

Bloom syndrome

A
  • susceptible to carcinomas, leukemias, and lymphomas
  • facial telangiectases, chromosome alterations
  • sensitive to mild alkylating agents
  • caused by mutation in BLM, RecQ helicase that functions in replication stress response
  • can also get progeria
28
Q

TDP1 mutation

A
  • Tyrosyl DNA phosphodiesterase

- SCAN1- spinocerebellar ataxia with axonal neuropathy 1

29
Q

APTX mutation

A
  • nucleotide hydrolase/transferase

- Ataxia oculomotor apraxia 1 (AOA1)

30
Q

DNA ligase I mutation

A

-immunodeficiency, defects in repair of DNA breaks induced by UV

31
Q

DNA ligase IV mutation

A

-Lig4 syndrome (immunodeficiency, radiosensitivity, pancytopenia, developmental abnormalities, microcephaly

32
Q

FEN1 mutation

A
  • cancer susceptibility

- autoimmune problems (Okazakis accumulate and act as antigens

33
Q

pre-replication complex mutation (ORC1, ORC4, ORC6, CDT1 CDC6)

A

-Meier-Gorlin syndrome- dwarfism

34
Q

anti-cancer: replication inhibitors

A
  • nucleotide analog chain terminators- AZT, ddC, ddl

- enzyme inhibitors- hydroxyurea (RNR_, camptothecin (topo I), 5-FU (thymidylate synthesis)

35
Q

DNA damage

A
  • spontaneous events
  • exposure to environmental mutagens
  • DNA replication errors or stress
36
Q

DNA repair mechanisms:template independent damage-direct reversal

A
  • pyrimidine dimers-photoreactivation by photolyase (t-t dimers, no longer functional in humans)
  • alkylation- O-methylguanine methytransferase
37
Q

ssDNA damage repair (one intact copy)

A
  • base excision repair
  • nucleotide excision repair
  • mismatch repair
38
Q

dsDNA break repair

A
  • homologous recombination
  • single strand annealing
  • non-homologous end joining
39
Q

BER, NER, MMR

A
  1. altered portion of DNA strand is recognized and removed by enzymes called DNA repair nucleases- hydrolyze phosphodiester bonds- small gap left behind
  2. DNA pol binds to the 3’-OH end of the cut DNA and fills in the gap by making a complementary copy of the information stored in the good strand
  3. break or nick left when DNA pol leaves is sealed by ligase

*first step differs by what enzyme does the removing

40
Q

ds break repair

A

-HR and NHEJ

41
Q

Homologous recombination

A
  • dsDNA exonucleolytically processed to form 3’ ssDNA tails, which invade homologous intact sequences. DNA strand exchange generates a joint molecule b/n damaged and undamaged duplex DNAs
  • sequence info that is missing is restored by DNA synthesis
  • interlinked molecules processed by branch migration, holliday junction resolution and DNA ligation
42
Q

single strand annealing

A
  • at DSB, 3’ ssDNA tails (direct repeats) generated

- they are aligned and the intervening sequences as well as protruding 3’ ends are removed

43
Q

NHEJ

A
  • broken DNA ends are processed to yield appropriate substrates for direct ligation
  • no homology necessary
  • breaks can be joined accurately but sometimes some insertions or deletions are created
  • preferred by humans
  • DSB= Ku protein–cascade–look at picture
44
Q

-xeroderma pigmentosum

A
  • severe predisposition to skin cancers
  • seven genetic complementation groups- XP-A to XP-G have been identified and associated with defective nucleotide excision repair
  • loss of function in XPV also results in XP, but not associated with NER but defects in lesion bypass of UV induced damage
45
Q

Nijmegen breakage syndrome

A
  • gamma iradiation sensitivity
  • DSB repair problem
  • lymphomas, microcephaly, short stature, distinct facial appearance, immunodeficiency, radiation sensitivity
46
Q

cockayne syndrome

A
  • UV light sensitive
  • NER problem
  • dwarfism, retinal atrophy, photosensitivity, progeria, deafness, trisomy 10
47
Q

fanconi anemia

A
  • cross linking agent sensitivity
  • FANCD1, 2 mutation
  • leukemias, hypoplastic pancytopenia
48
Q

breast and ovarian cancer

A
  • ionizing radiation and other genotoxin sensitivity
  • BRCA1 and 2
  • hereditary breast and ovarian cancer

MCP Unit 2 (10 decks)

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