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Biochemistry > Exam 2 Lecture 16 > Flashcards

Exam 2 Lecture 16 Flashcards

1
Q

What does it mean when replication is considered to be semiconservative?

A

It means that there is one parent strand and one new strand

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2
Q

What are the steps of replication?

A
  1. Unwinding
  2. Primer synthesis
  3. Elongation
  4. Okazaki fragments
  5. Ligation
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3
Q

During DNA replication, how many chromosomes are replicated?

A

All 46 chromosomes are replicated

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4
Q

DNA transcription is what of the cell cycle?

A

Independent

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5
Q

What is the first step in DNA replication?

A

DNA melting that will initiate replication and generate replication forks

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6
Q

How many origins of replications (ori) do humans have?

A

Multiple (around 6*10^4 ori): they are located 50-100 kbp intervals on each chromosomes and consist of AT rich regions, is bi-directional in which 2 diverging replication forks grow until they nearly merge

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7
Q

What is the role of topoisomerase II?

A

It is essential for termination and segregation of chromosomes

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8
Q

What is licensing?

A

Permitting the proteins at an origin of replication to begin DNA replication → only want this to happen once per cell cycle

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9
Q

What is the ORC and what does it do?

A

The ORC is the origin of replication complex that consists of 6 proteins from ORC1 to ORC6 which bind to the DNA at the origins throughout the cell cycle (so not just the S phase)

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10
Q

What is the MCM?

A

It is the minichromosome maintenance complex that consists of 6 proteins from MCM2 to MCM7. It is a licensing factor.

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11
Q

What happens when the ORC/MCM are activated?

A

2 replication forks are generated and replication is underway

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12
Q

What does helicase do?

A

It unwinds the DNA

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13
Q

What do single strand binding proteins (SSB proteins) do?

A

They prevent double stranded DNA from reassembling (example is RPA)

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14
Q

What is the importance of CDK phosphorylation on the activation of the ORC/MCM?

A

Phosphorylation prevents the assembly of a new ORC/MCM and ensure that replication won’t be initiated again → limits one license for replication per cell division

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15
Q

When is the preinitiation complex formed?

A

During G1 phase

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16
Q

How does the preinitiation complex form?

A

The licensing factors CTD1 and CDC6 are recruited to the ORC to form the preinitiation complex → this is important to limit DNA replication to once per cell cycle → MCM2-7 helicase complexes are loaded (2 per ORC) to fully form the preinitiation complex

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17
Q

When does activation of replication occur?

A

During the S phase

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18
Q

The cell cycle kinases CDK2 and DDK phosphorylate which licensing factors?

A

MCM, Cdc6, and Ctd1

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19
Q

What are the effects of phosphorylation?

A
  1. Cdc6 and cdt1 get released
  2. MCM helicase gets activated
  3. Phosphorylated forms can’t license a second round of DNA replication → will get degraded
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20
Q

What is the effect of the addition of Cdc45 and GINS?

A

They open up the replication fork to single stranded DNA and create the formation of 2 diverging replication forks

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21
Q

What role does replication protein A (RPA) play?

A

It stabilizes single stranded DNA

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22
Q

Replication occurs in which direction?

A

5’ → 3’

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23
Q

What is the role of a clamp loader?

A

It keeps the DNA intact (an example is replication factor C)

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24
Q

What is the role of a sliding clamp?

A

DNA polymerases bind to the sliding clamp complex (RFC/PCNA) and is converted into processive enzymes → makes the DNA polymerase be able to chug along and synthesize DNA (example is proliferating cell nuclear antigen aka PCNA)

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25
Replication occurs until what?
Until replicons meet and fuse
26
What does the replisome consist of?
2 polymerase III holoenzymes, the primosome, and DNA unwinding proteins
27
The DNA polymerases with the sliding clamps are associated as a what?
Associated as a dimer and are oriented in the same direction
28
How does the lagging strand compensate to make the DNA polymerases be oriented in the same direction?
It has to loop around in which the loops shrinks and grows (resembles a trombone)
29
How is replication regulated?
By CDKs that are activated by binding to cyclins → the expression of cyclins is controlled throughout the cell cycle
30
When is cyclin A transcribed?
At the start of DNA synthesis → transcription is mediated by cAMP and mitogen growth factors → involves transcription factor E2F and the loss of repressing gene transcription
31
Cyclin A is indirectly regulated by what?
Tumor suppressor protein p53 and the enhancement of p21 levels during cell cycle arrest → want lower cyclin a levels during cell cycle arrest in which p21 prevents the de-repression of cyclin A gene transcription by inhibiting E2F function
32
Different CDKs are activated by different...
cyclins
33
What causes cancer?
Deleterious changes in the genome that can lead to unregulated excessive division of cells such as dysfunction in DNA repair
34
How are oncogenes associated with cancer?
They are overexpressed and activated by mutation or recombination, they have increased gene copy number and promotes cell division (examples include BCR-ABL and c-myc)
35
How are tumor suppressor genes related to cancer?
They silence or reduce expression and are mutationally inactivated so they could potentially delete genes (examples include p53, BRCA1, and APC)
36
Cancers are usually susceptible to what kinds of agents?
Agents that damage DNA
37
What is the role of p53 in normal cells?
They scan the DNA for damage and can activate DNA repair or initiate apoptosis → play a role in stabilizing the genome sequence and preventing mutations
38
What happens when p53 is mutated?
The control system does not occur so the cell cycle does not arrest and DNA replication will continue to produce DNA with large amounts of damage
39
What is the inactive form of p53?
When it is bound to MDM2
40
What are the most successful approaches to inhibit DNA replication?
Inhibit biosynthesis of the DNA building blocks such as dATP, dGTP, dCTP, and dTTP → particularly successful target is the synthesis of dTMP from dUMP by thymidylate synthase (TS)
41
What are the 2 agents that can inhibit TS?
1. 5-flurouracil (5FU) | 2. Methotrexate
42
What does 5-FU do?
It is enzymatically converted to 5-fluro-dUMP which is a strong direct inhibitor of TS
43
What does methotrexate do?
It inhibits the synthesis of methylene tetrahydrofolate by inhibiting DHFR → an indirect inhibiting method since tetrahydrofolate is an essential co-enzyme of TS
44
How does HIV work?
It releases RNA into cells and reverse transcriptase can convert the RNA to DNA since it lacks proofreading activity
44
How does HIV work?
It releases RNA into cells and reverse transcriptase can convert the RNA to DNA
45
How can we target viral replication?
Reverse transcriptase! We can use an RT inhibitor with retroviral drug of a different class
46
What is the significance of AZT (azidothymidine)?
The time it took from the first time AZT was active against HIV in the lab to its approval was 25 months with is the shortest period of drug development in recent history
47
How are mutations caused?
By metabolic activities or environmental exposures on DNA
48
What is the natural rate of mutation?
1 mutation per 100,000 genes per generation
49
What are some types of DNA repair?
1. base excision repair 2. nucleotide excision repair 3. transcription coupled repair 4. post-replication (recombinational) repair 5. mismatch repair 6. double-strand break repair 7. direct damage reversal (photoreactivation) or removal
50
What is base excision repair?
Repairs apurinic sites, small damage caused by deamination or methylation, and removes uracil bases
51
What is nucleotide excision repair?
Repairs large damage such as bulky additions or pyrimidine dimers
52
What is direct damage reversal (photoreactivation)?
Removes a methyl from O6-methylguanine by MGMT
53
Why are cancer cells more easily poisoned by DNA-damaging (genotoxic) agents than normal cells?
They can't repair the DNA damage that occurs
54
What are some examples of genotoxic agents?
Cyclophosphamide, Cisplatin, Bleomycin, and topoisomerase inhibitors
55
What do alkylating agents do?
They halt replication by the cross-link between DNA strands by binding to guanine and alkylating it to induce double strand breaks (was used as a chemotherapeutic and sulfur mustard)
56
How are alkylating agents used today?
They are now used as platinum-based chemotherapeutic drugs such as Cisplatin and used in combo with other drugs like vinblastine and bleomycin to increase the survival rate of patients with testicular cancer
57
What is DNA recombination?
The rearrangement of DNA sequences by exchanging segments from different molecules (from one region to another)
58
What are the two main types of recombination?
General recombination and site-specific recombination
59
What is general recombination?
Occurs between homologous DNA molecules (common in meiosis in all cells), homologous recombination, occurs in all living organisms
60
What is site-specific recombination?
The exchange of sequences with only short regions of DNA homology, observed in transposition variation, only observed in bacteriophage DNA integration into E. coli DNA (so only in bacteria and bacteriophages)
61
What is the unequal exchange of the Philadelphia chromosome and BCR-ABL?
There is unequal exchange in the recombination of chromosomes 9 and 22 in which chromosome 22 is shortened and the ABL (tyrosine kinase) gene from chromosome 9 us immediately after the BCR gene on chromosome 22
62
What is the consequence of unequal exchange of chromosomes 9 and 22?
The Abl kinase region with auto-inhibition is lost so it is constitutively active → signals for cell proliferation if no stimulatory cytokine factor is present
63
Where is the Philadelphia chromosome and BCR-ABL found?
In cases of chronic myelogenous leukemia (CML) → Gleevac (imatinib), dasatinib, and Nilotinib inhibit BCR-ABL and can cure cases of CML
64
Replication is initiated at numerous origin sites spaced how far apart?
10^5 bp apart

Biochemistry (18 decks)

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