Biochemistry Section 2 chapters 1-

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coltondean
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Biochemistry Section 2 chapters 1-
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2011-09-05 18:52:28
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  1. Is a single or double mutation event required to create an oncogene? stop a tumor suppressor gene?
    Single, Double
  2. Describe how FAP is inherited and what happens in FAP patients that leads to early colon cancer?
    Autosomal dominant mutation in an APC allele. Loss of 2nd allele occurs in the second or third decade of life and leads to colon cancer in practically every patient.
  3. What is the gatekeeper for normal colon epithelial cell function
    The Wnt pathway.
  4. What are the regulatory proteins or genes in the Wnt pathway?
    • APC - tumor suppressor gene
    • beta-catenin - proto-oncogene
  5. Kinetochore proteins
    Mediate binding of microtubules to sister chromatids
  6. sister chromatids
    duplicated chromosomes
  7. centrosomes
    where sister chromatids attach and where the kinetochore proteins are located.
  8. cohesions
    proteins that hold sister chromatids together in the centrosome
  9. separase
    degrades cohesion proteins and seperates the sister chromatids
  10. securin
    binds seperase and prevents it from degrading cohesion
  11. cyclin-dependent kinases (Cdks)
    Engines of the Cell cycle, needs to be activated by cyclin before it can proceed.
  12. DNA Damage trips what checkpoints?
    G1/S transition, S-phase and G2/M transition
  13. anueploidy
    occurs when the cell fails to delay anaphase until all of the kinectochore microtubules are connected.
  14. How is the restriction into S-phase over come when a cell needs to replicate and divide?
    Signal binds and triggers the RAS-MAP kinase pathway.
  15. What is the difference between apoptosis and necrosis?
    Apoptosis is natural cell death, while necrosis leaks cell contents into the ECM and provokes an inflammatory response.
  16. How are caspases synthesized?
    pro-proteins
  17. How are caspases activated?
    • the procaspase is cleaved by initiator caspases and the prodomains are realeased. the caspase then reorganizes into a pair of heterodimers and associates with another pair of heterodimers.
  18. What makes up an apoptosome and what is it's function?
    • Cytochrome c released from the mitochondria recruit Apaf-1 and pro-caspase 9 to form an apoptosome.
    • It facilitates the auto-cleavage of pro-caspase 9 to caspase-9, which initiates the caspase cascade.
  19. How is apoptosis accomplished without caspases?
    • Ceramide (phospholipid produced by sphingomyelinases) is an apoptotic inducer.,
    • ROS can directly damage membranes and proteins,
    • and mitochondria can release nucleases that cleave chromatin.
  20. What is the role of p14/Arf
    phosphorylates and deactivates Mdm2
  21. What is the role of CHK?
    • Activated through phosphorylation by ATM/ATR and it activates p53 through phosphorylation.
    • It also phosphorylates Cdc25 which is then bound by 14-3-3 and inactivated.
  22. What are vectors in DNA recombination?
    Engineered DNA with bacterial origins whose function is to transport that DNA from one species to another.
  23. What is the function of restriction endonucleases?
    Cleaves DNA at a specific sequence. Can leave flush or sticky ends.
  24. What dictates the movement of different DNA strands in gel electrophorisis?
    Size
  25. Describe the GTPase activity of Ras and its subsequent effect.
    An activating signal binds to Ras and ATP displaces the GDP in the Ras-GDP complex and the kinase activity of Ras is activated. However, the GTPase activity of Ras hydrolyzed GTP to GDP which deactivates it. Thus a constant signal is required for continued activation of Ras.
  26. What are the four amino acids in the active site in Smac?
    A-V-P-I, and F was able to be substituted for I and still function.
  27. How does DNA Polymerase catalyze the formation of a 3'-5' phosphodiester bond?
    Through transesterification of an incoming triphosphate nucleotide.
  28. What kind of proofreading does DNA polymerase utilize and what is the accuracy of it?
    Displays 3'-5' exonuclease nuclease activity, the error frequency is 1/10^2 nucleotides. On top of an error frequency of 1/10^5 that DNA Polymerase has when it adds nucleotides.
  29. What protein complexes combine strand-directed mismatch repair and what is their error freq?
    Use Mut(S) and Mut(L) protein complexes to cut out a piece of DNA in the new strand when they detect mispaired bases. The error rate is 1/10^2. A mutation in these genes result patients getting colon cancer at an early age, called hereditary nonpolyposis colon cancer (HNPCC).
  30. How does DNA ligase join the 5' phosphate and 3' hydroxyl group?
    By activating the 5' end with an ATP, thus allowing the 3' OH group to nucleophilically attack and for the correct phosphodiester bond.
  31. What are some Drugs that target Topoisomerases?
    Bacteria: Nalidixic acid, Ciprofloxacin

    Leukemias: Etoposide (induces Topoiso. II-mediated DNA strand breaks and is a potent proapoptotic drug, can trigger chromosomal anomolies and secondary therapy related leukemias), Doxorubicin
  32. What does Pol-alpha/primase do during replication?
    Lays down a 10 base primer along with an additional 20 nucleotides on the lagging strand.
  33. How is the processivity of Pol-gamma and Pol-epsilon enhanced?
    With a sliding clamp, PCNA, which is loaded by RFC.
  34. What removes the RNA primers?
    RNase H and FEN1
  35. What is the role of maintenance methylase?
    It methylates the unmethylated strand at hemimethylated areas.
  36. What do some tumors use DNA methylation for?
    To inactivate some tumor suppressor genes.
  37. What are telomeres?
    Repeated G-rich sequences at the end of chromosomes.
  38. What is telomerase and what is its role Telomerase?
    Ribonucleoprotein that uses reverse transcriptase and extends the ends of chromosomes by recognizing the 3' end of telomeres and extending them. The RNA template is conserved and used repeatedly. Usually not expressed in differentiated cells.
  39. What is the mechanism of the anti-cancer drug methotrexate?
    Competative inhibitor of folate reductase (enzyme that produces precursers for purine and pyrimidine synthesis). Mutants can arise that are resistant to the drug with up to 100x more copies of the folate reductase gene. The result in vivo is the creation of tumors who are resistant and have increased their folate reductase gene through homogeneous staining regions (HSRs) which are repeated genes in a chromosome and DMs which are sub-fragments of a chromosome with the gene repeats.
  40. What occurs in depurination
    N-glycosyl bond is cleaved resulting in a loss of a purine and an apurinic site (AP).
  41. What kind of damage does UV light do to DNA
    creates cyclobuane dimers b/t adjacent pyrimidines.
  42. DNA Oxidation damage?
    converst F to 8-hydroxyguanine, which is highly mutagenic because it base pairs wrongly.
  43. What do Alkylating agents do to DNA?
    Methylate the bases, mechanism used by some anti-tumor drugs.
  44. What occurs when drugs and environmental factors create base adducts?
    Intra- and inter-strand crosslinks occur. The pro-carcinogen in cigarette smoke does this.
  45. How do ionizing rays (X-rays) damage DNA?
    Creating double-stranded breaks.
  46. Types of DNA damage
  47. Repeat expansion diseases, what causes them and what results from them.
    Slippage in DNA replication that results in the addition of repeat sequences called microsatellites. Fragile X syndrome
  48. Describe the process of Homologous recombination.
  49. What happens when unequal crossing-over occurs?
    repeated DNA sequences can mis-align and yield 'out-of-register' crossovers. These sequences are called LINES and SINES.
  50. What causes familial hyper-cholesterolemia?
    unequal crossover between Alu repeates the the LDL receptor gene.
  51. Describe the prosses of viral transpostion.
  52. How can viral transposition cause cancer?
    When the viral DNA is randomly inserted into the host DNA, it can disrupt key regulatory gene sequences and thus cause cancer. Also, some viruses have picked up oncogenes which get inserted into the host DNA as well.
  53. What is an example of conservative site-specific recombination? What happens?
    immunoglobulin genes and T-cell receptor genes are rearranged to give the immune system a greater variety of B-cell and T-cell function. This occurs when NHEJ is utilized by recombination activating genes (RAGS) and recombination signal sequences (RSSs).
  54. How does Human Burkitt's lymphoma occur?
    When the c-myc proto-oncogene on chromosome 8 gets translocated to the antibody heavey chain gene locus on chromosome 14.
  55. What is frequently mutated in melanoma?
    • Ras and Raf which are both components of the Ras/MAPK pathway. In melemoma the transcription factor Mitf (a master regulator of melanocyte cell fate) which leads to the upregulation of Bcl-2.
    • Ras also activates Akt via the PI3K/Akt pathway.
    • Also patients who inherit mutation in the Rb gene have a 50-fold increase of melanoma.
    • CDKN2A is a tumor suppressor gene that is freqently mutated in melanoma.
  56. What is the pre-initiator complex made of?
    RNA Pol II and GTFs
  57. What is the role of TFIID? TBP?
    • TFIID binds to DNA and recruits RNA Pol II along with the relevant transcription factors.
    • TBP is the domain in TFIID that binds to DNA in its MINOR groove. This creates a bend in the DNA that helps recruit transcription factors
  58. Describe the process of idling and promotor escape in transcription.
    • idling is when RNA Pol II repetivetly stops and restarts in an attempt to transcribe DNA.
    • It transistions from initiation to elongation when RNA Pol II sheds most of its initiaion factors, in an energy dependent process facilitated by ATPases, in favor of elongation factors. This is promotor escape.
  59. What is the Carboxyl Terminus Domain in RNA Pol II and what is its role?
    • composed of multiple 7 aa repeats
    • hyperphosphorylation leads to a massive rearrangement of the proteins associated with the CTD
    • Phospho of serine 5 by TFIIH is required for initiation and phospho of serine 2 by an elongation factor is required for elongation.
  60. What is the role of the mediator complex on CTD?
    • Allows regulatory proteins to associate with RNA Pol II
    • Left behind at the promotor
  61. How is transcription accomplished while DNA is still associated with histones?
    Through the use of chromatin remodeling complexes, SWI/SNF that shuffle nucleosomes around histones, alternatively exposing and covering DNA.
  62. What is the function of N-terminal tails of the histones?
    • Sites of many different covalent modifications, including acetylation, phosphorylation, methylation and ubiquitylation. (reversible)
    • Acetylation of lysine (acetyltransferase HAT) negates the positive charge and causes a more open chromatin, favoring transcription.
    • Methylation of lysine increases the hydrophobicity of the N-terminus
  63. What is the histone code?
    Hypothesized to be a code consisting of covalent histone tail modification which guides the interactions b/t DNA and proteins.
  64. Define Epigenetics.
    Changes in gene expression w/o changing DNA sequence.
  65. What do transcriptional activators do?
    Protein that binds to DNA (at enhancer) and stimulates the transcription of nearby genes.
  66. What part of RNA Pol II do activation factors bind to?
    Mediator complex, which is bound to RNA Pol II via the CTD.
  67. What two domains do transcriptional activators have?
    DNA binding Domain, and Activation Domain
  68. What do activational domains do?
    signal the ubiquiylation of many transcriptional activators. Why? Not sure.
  69. How do DNA-binding domains function?
    • Use an alpha-helix to "read" the chemical groups present in the major groove of DNA.
    • The different orientations of the chemical groups present in the major groove allow the DBD find the correct 4-12 bp sequence.
    • The DBD weakly interacts with the chemical groups and is thus able to "slide" along the DNA until the right seqence is found.
  70. How do the different families of DNA-binding proteins differ?
    In how the non-interacting sequence stabilizes the recognition helix.
  71. Why is cooperation b/t individual DNA-binding proteins necessary?
    because of the numerous identical 3-4 base pair sites that must exist in DNA. Thus multiple proteins are required to recognize a longer sequence.
  72. What are the three ways to regulate transcriptional activators?
    • Trapping the activator outside of the nucleus by interactions with a cytoplasmic protein or by anchoring the factor to a membrane.
    • Proteosome-mediated proteolysis, keeps the activator low by rapid proteolytic turnover under non-inducing conditions.
    • Regulation through post-translational modification and protein-protein interactions - similiar to proteosome-mediated proteolysis, just a less destructive regulation.
  73. What is an example of proteasome-mediated proteolysis?
    Ubiquitination of HIF-1 under normoxic conditions.
  74. What is an example of regulation through post-translational modification and protein-protein interactions?
    p53. Mdm2 normally interacts with the AD of p53 to prevent it from functioning. It also ubiquitinates p53 and marks it for destruction. When ATM/ATR phosphorylates p-53, it weakens its reaction to Mdm2
  75. How is the duration of a transactivator's function controlled?
    In these pathways, transcriptional activators must be mono-ubiquinated on certain lysine chains before it can be active. This leads to the destruction of the activator and requires a constant signal in order for the transcription to be expressed.
  76. What are two examples of pathways where the transcriptional pathway represses rather than acitvates a transcriptional activator?
    • Wnt pathway - signal leads to the survival of beta-catenin and the subsequent activation of activator TCF.
    • Notch pathway - signal leads to the cleavage of the Notch intracellular domain (NICD) which travels to the nucleus to allow CSL to activate transcription.

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