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Exam 4 Flashcards

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1
Q

Describe regulation of transcription in response to thyroid hormone

A
  • Thyroid hormone becomes bound to receptors that are constitutively in the nucleus and are bound to DNA elements of genes that respond to it - THR (receptor) when not bound to thyroid hormone is dimerized with RXR (retinoid X receptor) - This dimer recruits HDAC, which condenses chromatin and inhibits transcription - Binding of thyroid hormone triggers conformation change in THR, HDAC is released and HAT binds in its place, leads to relaxation of chromatin and enhancement of transcription - Response: stimulated metabolic rate in most tissues
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1
Q

Types of glycosylation. Describe

A
  • N-linked: starts in ER before protein folding is complete, adds sugars to Asn residues in protein in predictable fashion, modification of this can occur in Golgi - O-linked: starts in Golgi after protein folding is complete, adds sugars to serine or threonine residues, but not in predictable fashion
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1
Q

What is familial adenomatous polyposis? Outline the role of APC in the WNT signaling pathway. How does loss of APC function lead to cell proliferation?

A
  • Hereditary condition due to mutations in APC (adenomatous polyposis coli) gene that encodes tumor suppressor APC. Develop 100-1000s of adenomatous polyps. 100% of untreated FAP pts developed colorectal adenocarcinomas. Prophylactic colectomy is done - APC usually functions to down-regulate WNT signaling pathway - When mutation exists, WNT signaling is activated and expression of cyclin D, Myc and other growth-promoting genes occur - Additional mutations are implicated: oncogenic forms of Ras, may impact p53 function
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2
Q

Action of chloramphenicol

A
  • 70 S ribosome inhibitor - Specifically prevents peptidyl bond formation
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3
Q

Explain transportation from cytoplasm to nucleus

A
  • Ran-GTP bound to importin = inactivated Importin - Ran hydrolyzes GTP to GDP and importin dissociates, Ran-GDP moves into nucleus - Importin binds cargo and moves through nuclear pore complexes into nucleus - Ran-GDP in nucleus binds GTP and dislocates GDP - Importin dissociates from cargo in nucleus and associates with Ran-GTP moves out to cytoplasm
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3
Q

Name 3 antineoplastic agents that are inhibitors of DNA replication and repair

A
  • Cytarabine - Cyclophosphamide - Doxorubicin
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3
Q

What is the name of the molecule that synthesizes tRNA?

A
  • RNA Pol III
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3
Q

Describe the progression of ribosome assembly

A

1.) GTP binds eIF2a 2.) GTP:eIF2a becomes bound to Met-tRNA to form ternary complex 3.) 40S:eIF3 binds ternary complex (with eIF1 and eIF1alpha) 4.) mRNA now binds small subunit and pre-initiation complex is formed (with aid of eIF-4a, eIF-4b, eIF-4f, eIF-5 and PAB) 5.) eIF-5b:GTP are added to this complex displacing hydrolyzed GDP:eIF2a and 60 S subunit is recruited and positioned with met-tRNA in P site. Elongation can now ensue

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3
Q

Action of gentamicin

A
  • 70 S ribosome inhibitor - Specifically causes mistranslation of codons
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3
Q

Action of tetracycline

A
  • 70 S ribosome inhibitor - Specifically blocks A site and prevents tRNA binding
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3
Q

Describe role of ATM in G2/M checkpoint

A

1.) ATM kinase senses replication forks, which indicates ongoing replication, and prevents checkpoint kinase from allowing activation of Cdc25C, which normally dephosphorylates CDK1. Therefore CDK1 remains inactive. ATM remains active as long as replication forks active

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3
Q

In general terms, describe how activation of p53 leads to efflux of cytochrome c from the mitochondria, ultimately resulting in caspase activation and cell death.

A
  • ATM/ATR activity stabilizes p53 (remember, ATM and ATR are activated by double-stranded DNA breaks and UV light/damaging drugs respectively) - Targets of p53 include proapoptotic proteins belonging to Bcl-2 family - Bcl-2 family proteins (not Bcl-2, which is antiapoptotic) stimulates BAX activity, which promotes release of cytochrome c from mitochondria - Cytochrome c binds to Apaf-1 in cytoplasm - Oligomerization of cyt c with apaf-1 occur - This recruits caspase 9, initiator caspase - Caspase 9 activates executioner caspases, such as caspase 3 - Cell is destined to death
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3
Q

What is familial nonpolyposis colorectal carcinoma (HNPCC; Lynch syndrome)? Which genes are generally mutated in HNPCC? Which DNA repair pathway is impacted?

A
  • Hereditary susceptibility to colon cancer, 80% lifetime risk of colorectal carcinoma - Arises from defect in DNA mismatch repair (mutations to MSH2 or MLH1) genes - Pt inherits one defective allele from parent, loss or inactivation of second copy results in accumulation of mutations at accelerated rate typically in microsatellite repeats, which means microsatellite instability occurs - Microsatellite instability can reduce Bax protein function, which suppresses apoptosis and abnormal cells survive
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4
Q

Describe three processes that can lead to small insertions or deletions.

A

1.) Alignment out of registration, unequal crossover 2.) Strand slippage in replication as a result of repetitive sequences 3.) Intercalating agents causes slip bw stacked base pairs of DNA that distort helix and cause insertions or deletions

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4
Q

Describe repair of a pyrimidine dimer by process of nucleotide excision repair.

A
  • Helicases and nucleases work together to peel off region containing thymidine dimer lesion - DNA Pol and DNA ligase fill in gap
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4
Q

What GTFs are required by RNA Pol II?

A
  • TFIID binds to TATA box, which distorts the DNA helix, acts as signpost and recruits remainder of factors and pol II - Transcriptional initiation complex forms
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4
Q

How can epigenetic changes contribute to the development of cancers? Example

A
  • Increased methylation silences transcription of a gene, reducing tumor suppressor expression - Decreased methylation activates transcription of a gene, increasing production of oncoprotein - Example: INK4 promoter methylation suppresses transcription, preventing p16ink4 synthesis, allowing for continued phosphorylation of Rb by cyclin-D:CDK4/6 and cell proliferation
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5
Q

What is polyadenylation? Describe. What types of RNA molecule are polyadenylated?

A
  • Polyadenylation = addition of 100s of adenine residues to end of mRNA moledule - Stop pt for transcription is specified by a consensus seq in DNA known as polyadenylation signal, which is transcribed into pre-mRNA - This signal is recognized by specific protein factors - This tail is important for RNA stability
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6
Q

Describe regulation of G1/S transition

A
  • S phase requires active cyclin A-CDK2, which is initially formed as inactive complex with inhibitor called p27kip1 - Late g1: cyclin E-CDK2 is desphosphorylated by phosphatase (Cdc25A) - cyclin E-CDK2 phosphorylates p27kip1 in complex w/ cyclin A-CDK2, cyclin A-CDK2 is activated by being freed from p27KIP2 - It promotes DNA replication by phosphorylating components of ori complexes
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7
Q

Describe the typical layout of a gene that is transcribed by RNA polymerase II

A
  • Enhancer (way upstream) - Gene-specific elements: DNA sequences unique to particular genes or groups of genes - CAAT box or GC-rich region: may be present - TATA box: almost invariably found in genes transcribed by Pol II - Gene
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8
Q

Discuss checkpoints of cell

A
  • G1/S = restriction point – checking if conditions are favorable for division - G2/M = has DNA been replicated and are conditions still favorable for division - Metaphase/anaphase transition point = are c/s all attached to mitotic spindles
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8
Q

Define proto-oncogene. How does mutation in these genes contribute to development of cancer?

A
  • Proto-oncogene: promote cell growth - Loss of function causes excessively active growth promotion = stuck accelerator = oncogene = typically dominant mutations
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9
Q

Examples of caretaker genes. Cancers resulting in defects from these genes

A
  • MSH2 or MLH1 code for DNA mismatch repair. Mutations lead to HNPCC: hereditary nonpolyposis colorectal carcinoma - BRCA1 or BRCA2 gene code for machinery involved in homologous recombination. Mutations lead to increased risk of breast/ovarian and cancer development. Unable to repair of double-stranded DNA breaks.
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10
Q

Charcot Marie Tooth Disease

A
  • Congenital chaperone defects cause protein folding disorder
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11
Q

Discuss rate of DNA transcription in context of basal transcription complex

A
  • Basal transcription complex = RNA pol II with GTFs - This complex initiates transcription at low rates - High rate requires NF1 binding to CAAT box and SP-1 binding to GC-rich sequences
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11
Q

Where are O-glycosylated proteins seen?

A
  • Proteoglycans of the ECM - H-antigen on surface of RBCs (predictable)
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11
Q

Describe ways by which ATM/ATR kinases can prevent cell cycle progression in the face of DNA damage.

A

1.) ATM is activated by double-stranded breaks 2.) ATR is activated by UV light and certain DNA-damaging drugs - Both kinases stabilize p53 - P53 upregulates p21cip1 - p21 inhibits activates a kinase that prevents cdc25a and cdc25C from activating cyclin A/E-CDK2 (S phase) and cyclin A/B-CDK1 (M phase) respectively. - ATM and ATR also activate a checkpoint kinase that prevents cdc25a and cdc25C from activating cdc25a and cdc25C from activating cyclin A/E-CDK2 (S phase) and cyclin A/B-CDK1 (M phase) respectively

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13
Q

What is the name of the molecule that synthesizes rRNA?

A
  • RNA pol I, some Pol III
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14
Q

What is the mechanism of action of tamoxifen?

A
  • Tamoxifen inhibits estrogen action - It is a competitive inhibitor, blocking estrogen binding to its receptor, however ERE dimer still remains dimerized and bound to DNA - Growth of breast cancer is reduced by disrupting this estrogen signaling
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14
Q

Names of 70S ribosome inhibitors

A
  • Streptomycin - Neomycin - Gentamicin - Tetracycline - Chloramphenicol
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15
Q

What are point mutations? How might point mutations arise? Distinguish bw silent, missense, and nonsense mutations.

A
  • Exchange of one nt for another - Caused by replication errors, chemical mutagens, radiation, DNA damage repair - Silent: no changes to AA - Missense: change from one AA to another - Nonsense: change from AA to stop codon
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16
Q

What is the target of the drug trastuzumab (Herceptin) used in the treatment of some breast cancers?

A
  • Binds to EC domain of Her2/Neu and is important inhibitor of tumor growth. - Mechanism? Inhibition of receptor dimerization and activation, induction of apoptosis, stimulation of antibody or complement-mediated cytotoxicity
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17
Q

Describe base excision repair process using the example of the removal of a cytosine residue that has been deaminated to uracil.

A
  • DNA glycosylases recognize diff types of altered bases in DNA and catalyze their hydrolytic removal - Cytosine spontaneously deaminated to uracil - Uracil DNA glycosylase removes uracil base creating AP site - AP endonuclease introduces nick - DNA phosphodiesterase removes remnant sugar and phosphate - DNA Pol and ligase fill in correct base
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18
Q

How is CDK4/6 activity inhibited

A
  • INK4 proteins inhibit these proteins. - INK4 transcription is stimulated by growth inhibitory factors
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19
Q

Explain how LDL receptor production changes in response to cholesterol. Discuss mechanism

A
  • Transcription of LDL receptor gene is upregulated in response to low cellular cholesterol - Result: more LDL receptor production and enhanced cholesterol uptake from blood Low-level transcription - SP1 (zinc-finger protein) binds to GC rich regions in LDL receptor promoter - SP1 requires CRSP protein cofactor to be activated - SP1 and CRSP help pol II and GTFS to assemble at promoter - These are all considered basal transcription factors Up-regulated transcription - Requires basal transcription factors - Also SREBP-1a enters into nucleus as triggered by low cellular cholesterol - SREBP-1a binds to SRE and recruits HAT activity plus some other proteins - Result = enhanced transcription of LDL-receptor gene
19
Q

How are proteins directed to lysosomes

A
  • Proteins directed to lysosome require phosphomannose
19
Q

Discuss how proteins can return to their interphase states after the M phase

A
  • APC causes degradation of cyclin A and B, which shuts off CDK1 activity and stops mitotic events from occurring - Desphosphorylation of cyclin-CDK targets by Cdc14 returns proteins to their interphase state: promotes decondensation of chromatin, disassembly of mitotic spindle, reassembly of nuclear membrane, cytokinesis) - APC becomes inactivated and Rb is dephosphorylated
20
Q

What is the two hit model? Describe this model in relation to the development of retinoblastoma. What is the normal function of Rb?

A
  • Tumor suppressor genes inhibit proliferation - Damage to both alleles must occur to allow unregulated proliferation as the genes are recessive - This is why it is called two hit model - Individuals inheriting one mutant allele of tumor suppressor gene are at increased risk for certain cancers. If somatic mutation in second allele, tumor growth will occur Retinoblastoma mutation: - Rb protein is phosphorylated by cyclin D-CDK4/6 or cyclin E-CDK2. When phosphorylated, drives cell cycle. - Inherited form: one mutant allele from parent, somatic mutation of second allele in retinal cell leads to retinoblastoma. Tumor tends to develop in infancy - Sporadic form: two separate somatic mutations in a retinal cell or its progeny produces retinal cell in which both copies of functional Rb are lost - Symptoms: Leukocoria = white pupil, represents calcified intraorbital masses
22
Q

What are the targets of nalidixic acid, cirprofloxacin and doxorubicin?

A
  • Nalidixic acid and ciprofloxacin act on bacterial topoisomerase II enzymes and function as antibiotics - Doxorubicin acts on human topoisomerase II and is used as an anticancer agent
24
Q

What roles do chromatin remodelling complexes, histone acetyltransferases (HATs), histone deacetylases (HDACs) and DNA methylation play in controlling the availability of genes for transcription?

A

1.) chromatin remodeling complexes: use ATP to change nucleosome structure temporarily to allow or inhibit transcription 2.) HATs: acetylate lysine residues in histones, reduce net pos charge of protein, weakens histone:DNA interaction, facilitates transcription 3.) HDACs: remove acetyl groups from histone, increasing net pos charge of protein, strengthens histone:DNA interaction, inhibits transcription 4.) DNA methylation: methyl groups added to cytosine, found in silent regions of genome, binds proteins that recruit HDACs to DNA, promoting condensation and inhibiting transcription

24
Q

Action of diphtheria toxin

A
  • protein produced by C. diphtheriae that inactivates EF-2 by ADP ribosylation, preventing elongation
27
Q

Discuss pre-mRNA splicing.

A
  • Catalyzed by complex known as spliceosome, which has protein and snRNA compoments involved in catalysis and recognizing exon/intron boundaries - Consensus nt seqs are required for splicing: 5’ splice site, 3’ splice site and branch point within intron - Adenine at branch point attacks 5’ splice site, cutting sugar-phosphate backbone of RNA - 5’ end becomes linked to adenine, forms a loop - Free 3’OH reacts with 5’ end of next exon, joins. Intron released as lariat
29
Q

How is ATM activated? Implication

A
  • ATM is activated by replication forks: when RFs are present, DNA replication is present and cell-cycle needs to be halted until this completes - ATM also activated by double-stranded breaks
30
Q

What is meant by the capping of pre-mRNA? Is the cap unique to pre-mRNA? Function?

A
  • Methylguanosine is added to the 5’ end of pre-RNA - This distinguishes mRNA from other types of RNA - Required for subsequent processing steps - Protects against degradation - Important for initiation of translation
31
Q

Name three common DNA lesions

A
  • Depurination: bond bw base and ribose hydrolyzed - Deamination: most often cytosine deamination generates uracil - Pyrimidine dimers: UV light dimerizes adjacent thymine bases on same DNA strand
33
Q

Outline the steps involved in replication of DNA

A
  1. Origin recognition complex proteins bind to origins – ORC activated s phase, then inactivated until after mitosis 2. DNA helicase unwind the double helix 3. SSBPs bind DNA and prevent reformation of double helix 4. Tension in DNA acted on by topoisomerase I, which cuts phosphodiester bond of one strand and allows strand to rotate, religation occurs 5. Primase activity of DNA pol alpha uses exposes SS DNA region as template to synthesize a short complimentary stretch of RNA, provides 3’ OH 6. DNA pol alpha is replaced by delta or epsilon 7. Protein complex known as sliding clamp is loaded onto DNA, facilitates pol activity 8. DNA pol replicates continuously on leading strand, discontinuously (delta) on lagging strand 9. RNase activity removes primer, DNA pol possibly delta fills in gap left by primer removal 10. DNA ligase joins Okazaki fragments
34
Q

How do growth factors stimulate cell division? Discuss growth factor binding and all intracellular pathway

A

1.) Binding growth factor stimulates dimerization and autophosphorylation on the tyrosine residues of the receptors (growth factor receptors contain intrinsic protein tyrosine kinase activity). 2.) Phosphorylation residues form docking sites*. 3.) Adaptor protein GRB2 binds phosphotyrosine, which recruits guanine nucleotide exchange factor Sos, which activate 4.) Sos activates g-protein Ras by promoting exchange of GDP (Ras + GDP = inactive) for GTP (Ras + GTP = active) 5.) Ras then activates Raf (aka MAP kinase kinase kinase) 6.) Raf activates MAP kinase kinase (aka MEK) by phosphorylating it 7.) MAP kinase kinase activates MAP kinase through phosphosphorylations, which translocates into the nucleus to regulate transcription of many genes, including stimulation transcription of gene encoding c-Fos 8.) c-Fos stimulates transcription of cyclin D, CDK4/6 9.) Cyclin D, CDK4/6 phosphorylates Rb (retinoblastoma) in Rb:E2F complex, causing dissociation of Rb from E2F. 10.) E2F is a transcriptional activator of cyclin E/CDK2 (late G1 cyclin), which also acts to phosphorylate Rb:E2F as in 9. E2F also is a transcriptional activator of cyclin A (s-phase cyclin) * Most signal Ras/MAP kinase pathway

36
Q

Explain the regulation of translation

A
  • Points of regulation are at 1.) recognition of start codon and 2.) activity of initiation factors 1.) Recognition of start codon: bind of regulatory protein in 5’ UTR can mask start codon 2.) eIF-2a can be inactivated by phosphorylation
38
Q

Define tumor suppressor. How does mutation in these genes contribute to development of cancer?

A
  • Tumor suppressor: inhibit cell growth - Loss of function relieves growth inhibition = non-functioning brake pedal, typically recessive mutations
41
Q

How can rifampicin kill certain bacteria yet have low toxicity towards human cells?

A
  • Used to treat mycobacterial infections such as TB and leprosy - It is a specific inhibitor of RNA pol found in many types of bacteria, but euk Pol II is not sensitive to it
42
Q

What is Li-Fraumeni syndrome?

A
  • Dominant heritable condition conferring increased susceptibility to many forms of cancer as a result of dominant negative effect of mutation to TP53 allele - Cells with damaged DNA are free to continue to divide and tumors develop
43
Q

What is ataxia telangiectasia?

A
  • Rare inherited disorder resulting from mutations in gene that encodes ATM kinase - Symptoms: difficulty in coordinating movement (ataxia) and appearance in small, widened blood vessels on skin (telangiectasia) - Pts susceptible to infections and at increased risk of leukemias and lymphomas. They are highly sensitive to radiation exposure.
44
Q

What is CML and what is the biochemistry behind it? What gene fusion is generated? What is the biochemical activity associated with the fusion protein? Treatment?

A
  • CML = chronic myelogenous leukemia - Result of translocation bw c/s 9 and 22, fuses the ABL gene usually on 9 to the BCR gene on 22, creating Philadelphia chromosome BCR-ABL on 22 - Result = constitutively active Bcr-Abl kinase can phosphorylate many targes. In hematopoietic cells, stimulates expansion of white blood cells - Treatment = imatinib mesylate (Gleevec) is specific inhibitor of this kinase
46
Q

Action of streptomycin

A
  • 70 S ribosome inhibitor - Specifically binds to small subunit (30 S) and inhibits initiation and causes mistranslation of codons
48
Q

Outline the process of strand-directed mismatch repair.

A
  • Newly synthesized DNA contains nicks, which distinguishes parental and daughter strands - Base mismatch distort DNA helical structure - Repair enzymes recognize distortion and remove mismatched base, excise nucleotides back to nearest nick - Gap fill by DNA pol using parental DNA strand as template
49
Q

How is entry into mitosis coupled to completion of DNA replication?

A
  • Completion of DNA replication activates protein phosphatase (cdc25C) - Protein phosphatase dephosphorylates a particular tyrosine residue in CDK1, which activates cyclin A or B-CDK1 complexes - Cyclin A or B-CDK1 complexes phosphorylate many proteins that participate in early mitotic events including chromosome condensation, assembly of mitotic spindle and breakdown of nuclear membrane
51
Q

Action of neomycin

A
  • 70 S ribosome inhibitor - Specifically causes mistranslation of codons
52
Q

What is Rubinstein-Taybi syndrome?

A
  • Inherited condition characterized by hypoplastic maxillar (insufficient growth of midface), prominent nose, intellectual disability, polydactyly, growth retardation - Results from mutation in gene encoding CREB binding protein (CBP) - This gene is implicated in processes related to memory, cognition and developmental processes
53
Q

What is HIF-1alphabeta and how is it regulated? What is the importance of HIF-1alphabeta in the growth of tumors?

A
  • In normoxic environment, HIF-1alpha (hypoxia-inducible-factor) is hydroxylated by proline hydroxylase, leading to accumulation and destruction of itself - In hypoxic environment, HIF-1alpha associates with HIF-1beta, which regulates expression of VEGF and many other genes, allowing for angiogenesis to proceed. - Result = new blood supply delivers nutrients/oxygen, removes waste to/from tumors
55
Q

By what mechanism does the toxin alpha-amantin function? How are ppl exposed to this? Symptoms? Treatment?

A
  • Death cap mushroom common in cool, damp regions of pacific coast - Genus/species: amanita phalloides - Contains alpha-amantin, which is a Pol II inhibitor - Nausea, vomiting, coma, hepatic encephalopathy from liver failure - Liver failure ~ 48 hour post-ingestion - Tx: gastric lavage, activated charcoal and liver transplant
55
Q

What is Burkitt’s Lymphoma? Describe biochemistry that causes it.

A
  • Translocation event moves c-myc gene from normal position on c/s #8 over to c/s #14 - Result = myc gene is now near control elements of antibody HC and continuous production of high levels of Myc occurs in B-cells. B-cells become cancerous
56
Q

Would a normal cell divide if chromosomes were not correctly attached to the mitotic spindle? Explain

A
  • No - Anaphase of mitosis is delayed until chromosomes attach to mitotic spindle - Correct assembly of mitotic spindle activates anaphase promoting complex (APC) - APC allows degradation of cohesin complexes, which hold sister chromatids together at centromere, sister chromatids can move to opposite poles - APC acquires different subunit and causes degradation of cyclin A or B
57
Q

Explain transportation from nucleus to cytoplasm

A
  • Ran-GDP binds GTP and dissociates from GDP forming Ran-GTP - Ran-GTP binds exportin, binds cargo and moves through nuclear pore complex into cytoplasm - Hydrolysis of complex occurs, Cargo, exportin and Ran-GDP dissociate, Ran-GDP returns into nucleus
58
Q

What is neurofibromatosis I? What is normal function of the protein?

A
  • Symptoms/signs: café au lait spots, multiple non-malignant peripheral nerve tumors (neurofibromas) and iris Lisch nodules - Result of loss of function mutation in NF1 gene (recessive) that encodes neurofibromin that normally accelerates rate of GTP hydrolysis by Ras, causing it to be in inactive form - Lack of NF1 gene function prolongs Ras signaling increases proliferation through MAP kinase pathway
61
Q

Outline mechanism of action of the chemotherapeutic agents cytarabine, cyclophosphamide, and doxorubicin.

A

1.) Cytarabine is an analogue of cytidine, contains arabinose in place of ribose. Converted to cytarabine triphosphate. Competes with dNTPs for binding to DNA polymerase 2.) Cyclophosphamide is converted to phosphoramide mustard by liver. It is a bi-functional alkylating agent that forms inter and intra strand DNA crosslinks that block replication and can trigger apoptosis 3.) Doxorubicin form tripartite complex with DNA and topo II. Topo II introduces D-S breaks in DNA. Binding doxorubicin prevents re-ligation of D-S breaks. Breaks accumulate and trigger apoptosis

63
Q

How does the steroid hormone cortisol regulate transcription?

A
  • Cortisol is secreted by adrenal cortex - Binds to and activates receptors in cytoplasm, causing conformational change to that receptor - Accessory proteins dissociate, activated receptors dimerize - Dimerized receptors are imported into nucleus - Bind GRE elements on genome, regulate transcription positively or negatively - Typical result of cortisol is to stimulate gluconeogenesis, glycogen deposition, fat and protein degradation, inhibit inflammatory response
65
Q

Describe role of p53 in triggering cell cycle arrest or apoptosis in response to DNA damage. What gene encodes it?

A
  • p53 is normally an unstable protein, is ubiquinated and destroyed by proteasome when not stabilized - Phosphorylation by ATM/ATR (double-stranded breaks or UV damage respectively) increases stability of it, which leads to transcriptional control of many genes that regulate cell cycle arrest, repair of DNA and apoptosis - Encoded by gene TP53 - Active p53 is homotetramer. Missense mutations in one allele greatly reduce function. Any subunit mutation of the tetramer will cause aberrant function. Mutations act as dominant negative
67
Q

What is the name of the molecule that synthesizes mRNA?

A
  • RNA pol II
68
Q

Why are double-strand DNA breaks particularly troublesome? What two avenues of repair are available? Explain what each does.

A
  • No intact template / parental strand to direct repair - Nonhomologous end-joining: broken ends processed, loss of nucleotides at breakpoint, brought together, ligated, ends with permanent change in DNA sequence - Homologous end-joining: repair of damaged chromosome using information contained in undamaged, homologous chromosomes, allows repair of d-s breaks without loss of information
69
Q

Describe N-linked glycosylation mechanism

A
  • Dolichol phosphate in ER membrane acts as site for oligosaccharide in ER - Glycosyltransferase adds two GlcNAcs to dolichol - Glycosyltransferase adds five mannose - Dolichol phosphate linked to above CHOs reorientates from cytoplasm into ER lumen - 4 more mannoses are added onto oligosaccharide using dolicholphosphomannose - 3 glucoses are added to mannose forming universal oligosaccharide containing 14 sugars - Highly specific modification of universal oligosaccharide occurs in Golgi apparatus by addition or removal of CHOs, yielding high mannose type or complex type (sialic acid, fucose, N-acetyl glucosamine, N-acetyl-galactosamine, galactose)
70
Q

Which polymerase has proofreading activity?

A
  • DNA Pol delta
72
Q

Outline the changes that must occur before normal cells of the colon can develop into an adenoma and then a carcinoma.

A
  • FAP pts inherit one defective allele from parent - Inactivation/loss of second allele occurs = - Proto-oncogene mutation, typically in Ras and loss of tumor suppressor genes typically TP53 causes adenomas - Additional mutations, gross c/smal changes, increased telomerase leads to carcinoma
73
Q

Describe elongation and termination of translation

A

1.) EF-1-GTP charges tRNA molecule (EF1-GDP = product). AA-tRNA moves into A site 2.) Peptide bond formation occurs 3.) EF-2-GTP hydrolysis allows ribosomal complex to move one codon down with mRNA-peptidyl-complex now occupying the P site and the A site is empty. Uncharged tRNA leaves through E site 4.) Ribosome is now ready to repeat the cycle 5.) Once the stop codon is moved into the A site, eRF bound to GTP is hydrolyzed and the ribosomal complex dissociates

74
Q

The cell cycle is driven by the activity of cyclin-dependent kinases. Which cyclin-CDK complexes are most important at: a.) M-phase b.) Mid G1 phase c.) Late G1 phase d.) S phase

A

1.) M-phase: cyclin A/CDK1 and cyclin B/CDK1 2.) Mid G1 phase: cyclin D/CDK4 and cyclin D/CDK6 3.) Late G1 phase: cyclin E/CDK2 4.) S phase: cyclin A/CDK2

75
Q

What is xeroderma pigmentosum and what cause it?

A
  • Extreme sensitivity of the skin to sunlight - Pigmentation changes, skin cancers, develop on areas exposed to sun - Result from any of several mutations that impair or abolish the nucleotide excision repair
76
Q

Describe the factors that determine protein half-life

A
  • Conformation: eg. Misfolding results in hydrophobic domains being placed on surface and leads to degradation - N-terminus: Ser/Met proteins are more stable than Arg/Lys proteins - Other sequences: eg. PEST sequences shorten lifespan
77
Q

Describe beta-thalassemia

A
  • Reduced beta-chain of hemoglobin due to mutation in beta-globin gene at first exon/intron boundary. Mutation at 5’ splice site causes two aberrant mRNA products to be formed
78
Q

Discuss roles of the CREB, CBP and PKA in transcriptional control

A
  • PKA phosphorylates and regulates many cytosolic proteins, but is also present in activated form in nucleus under high levels of cAMP - Many genes regulated by PKA contain CRE (cAMP responsive element) in their promoter region - PKA influences transcription by phosphorylation of CREB, which then binds CRE - CREB bound to CRE recruits CBP - CBP then recruits EP300 - CBP/EP300 interacts physically with GTFs. Together CBP/EP300 function as HATs, relaxing chromatin and stimulating transcription
79
Q

Describe how the receptor tyrosine kinases HER2 and ErbB1 can be converted into constitutively active forms that function as oncoproteins

A
  • HER2 (aka Neu): point mutation allows activation of kinase in the absence of ligand - ErbB1: deletion of ligand bind domain results in constitutive activation of kinase domain
80
Q

RBC surface antigens. Core? Sugar residues for O, A and B antigen?

A
  • Core: Serine – Gal – GlcNAc – Gal X – Fucose - O: Serine – Gal – GlcNAc – Gal X – Fucose - A: Core – Gal X attached to GalNAc as well as Fucose - B: Core – Gal X attached to Gal as well as Fucose
81
Q

Describe biochemistry behind HPV-induced cervical cancer

A
  • HPV virus produces E6 and E7 proteins that target p53 and Rb respectively leading to ubiqutination
82
Q

Why is phosphorylation of Rb such as crucial event in cell cycle progression? Which kinases phosphorylate Rb?

A
  • Phosphorylation of Rb in Rb:E2F by cyclin D:CDK4/6 causes dissociation of Rb from E2F - E2F is a transcriptional activator of cyclin E:CDK2 - In the absence of growth factors, Rb phosphorylation can still occur independent of cyclin D:CDK4/6 and cell cycle can progress
83
Q

Describe molecule basis for PKU

A
  • Inability to convert phenylalanine to tyrosine due to mutation often at 5’ splice donor site in phenylalanine hydroxylase gene - Results in defective splicing, protein produced lacks one exon and is rapidly degraded
84
Q

How are primers removed and Okazaki fragments joined together?

A
  • Specific RNase activity removes primer - DNA pol (possibly delta) fills in gap left by primer removal - DNA ligase uses ATP to seal Okazaki fragments
85
Q

What is I-cell disease? Describe the defect

A
  • Surface mannose residues are not phosphorylated and therefore lysosomal proteins don’t reach the correct compartment and appear in serum - Result: lysosomal degradation of proteins and CHOs is impaired, inclusion bodies are seen in lysosomes making them appear dense
86
Q

Action of ricin

A
  • potent ribosome inactivating protein (RIP) found in castor beans - it removes adenine bases from rRNA

Biochemistry & Molecular Biology (47 decks)

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