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8/9 Ch. 16, 17, 23.4 Notes

by: Hannah Kennedy

8/9 Ch. 16, 17, 23.4 Notes 30156

Hannah Kennedy
GPA 3.98

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About this Document

These notes cover everything in class as well as complementary book material regarding 16, 17, and 23.4
  Dr. Helen Piontkivska
Class Notes
Biology, Genetics, generegulation, cancer
25 ?





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This 12 page Class Notes was uploaded by Hannah Kennedy on Saturday August 13, 2016. The Class Notes belongs to 30156 at Kent State University taught by   Dr. Helen Piontkivska in Spring 2016. Since its upload, it has received 11 views. For similar materials see ELEMENTS OF GENETICS in Biological Sciences at Kent State University.


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Date Created: 08/13/16
© Hannah Kennedy, Kent State University 8/9 Lecture—Ch. 16, 17, 23 1. Catabolite-Activating Protein (CAP) positively controls the lac operon a. cAMP = small effector molecule produced from ATP via adenylyl cyclase b. Glucose is a byproduct of the cleaving of lactose i. When glucose is absent ii. When glucose is present 1. We still have some expression from lac operon but not at the same levels as before nd 2. Metabolized preferentially and the 2 sugar is metabolized after glucose is depleted for efficiency purposes 3. Transport of glucose into cell causes cAMP concentration to decrease because adenylyl cyclase is inhibited a. cAMP effect on lac operon is mediated by activator protein CAP c. When CAP binds to the promoter, it creates a ben greater than 90° in DNA making the RNA polymerase easier to interact with the operator d. CAP is made of 2 subunits 2. Roles of the lac repressor and CAP in the regulation of the lac operon a. Lactose, no glucose —high cAMP i. cAMP binds to CAP and CAP binds to CAP site and stimulates RNA polymerase to start transcription ii. high transcription rate b. no lactose, no glucose—high cAMP i. binding of the lac repressor inhibits transcription even though CAP is bound to DNA ii. low transcription rate due to repressor binding c. lactose, glucose—low cAMP i. lactose presence causes lac repressor to be inactive ii. presence of glucose decreases cAMP levels so cAMP is released from CAP preventing it from binding to CAP site iii. transcription is low due to lack of CAP binding d. glucose, no lactose—low cAMP i. low transcription rate due to lack of CAP binding and repressor binding 3. Negative vs. positive regulation or choosing the best sugar to metabolize a. Lac operon is regulated by 2 mechanisms based on the substrates in the environment i. (primary mechanism) Regulation that involves lactose is negative regulation therefore when repressor sits there everything is shut down ii. (secondary mechanism) Regulation that involves glucose is positive regulation therefore when CAP is there lac operon is sitting there, then sequestered by glucose and expression levels are diminished 4. Inducible vs. Repressible © Hannah Kennedy, Kent State University a. Inducible: digestion b. Repressible: synthesis i. when you are synthesizing something yourself so when you have access from an outside source you don’t need to synthesize it yourself 5. trp operon—repressible operon regulated by a corepressor that binds to repressor and turns operon off a. 5 genes are involved in tryptophan biosynthesis in E. coli i. O: regulatory region ii. trpE, trpD, trpC, trpB, and trpA = structural genes = encode enzymes that take common substrate and sequentially turn it into tryptophan AA iii. trpR = encodes the trp repressor 1. when tryptophan levels are low a. tryptophan doesn’t bind to repressor so the trp repressor can’t bind to the operator site and RNA polymerase transcribes the operon 2. when tryptophan levels are high a. tryptophan acts a corepressor and binds to the trp repressor protein which causes conformation change in repressor and allows it to bind to the operator which inhibits RNA polymerase to transcribe the operon iv. trpL = mediated the attenuation regulatory mechanism 1. attenuation is able to occur bc transcription and translation are coupled in prokaryotes 2. during attenuation a. transcription begins but is terminated before the entire mRNA is made b. mRNA from the trp operon is made as a short piece that terminates at the attenuator sequence (right after the trpL gene) i. this mRNA has been stopped before RNA polymerase has transcribed the structural genes so it doesn’t encode proteins needed for making of tryptophan b. regulation of trp operon i. negatively regulated operon because it works with a repressor ii. P = repressor c. When tryptophan is absent: © Hannah Kennedy, Kent State University i. the repressor is inactive and it can’t bind to operator therefore the genes are on and transcription is ongoing d. When tryptophan is present: i. Makes more sense to use it when it is presented to you than make it yourself so you don’t have to expend ATP so when it is present we will shut down the operon and halt transcription ii. Possible problem: running out of tryptophan therefore we need a mechanism that evaluates how low we are on tryptophan and whether or not we need to make more therefore attenuation comes into play e. Attenuation: bacteria modulate its gene expression; to make tryptophan, you need to have tryptophan in enzymes therefore it can ramp up production of its own enzymes i. Evaluates how long the ribosome waits for the charged tRNA with tryptophan to come in. When it takes longer, loops can form in tRNA ii. mRNAs that encode leader peptides are rich in codons for the specific AA that is made by enzymes encoded by particular codon iii. 2 key features of attenuation 1. 2 trp codons are found within the mRNA that encodes the trp leader peptide which provides a way to analyze if E.coli has enough trp to synthesize proteins 2. mRNA can form stem-loops a. 1-2 b. 2-3 © Hannah Kennedy, Kent State University c. 3-4 i. acts as an intrinsic terminator so it causes the RNA polymerase to pause and the U-rich sequence found here dissociates from the DNA causing termination of transcription ii. conditions that favor this formation rely on translation of trpL gene iv. 3 scenarios possible with stem loops 1. translation isn’t coupled with transcription a. region 1 bonds to region 2 b. region 3 h bonds to region 4 c. terminator stem-loop forms and transcription is terminated right past the trpL gene 2. coupled transcription and translation occur under low trp concentrations (therefore the cell cant make sufficient amount of charged tRNA )trp a. ribosome pauses at the trptrpdons in the trpL mRNA bc it is waiting for charged tRNA so the ribosome shields region 1 of the mRNA prevention 1 from H bonding with 2 so 2 h bonds with 3 and the 3-4 stem loop can’t happen i. bc the 3-4 stem loop doesn’t happen termination of transcription doesn’t happen and RNA polymerase transcribes rest of operon allowing bacteria to make more trp 3. coupled transcription and translation when a sufficient amt of trp is in the cell a. translation of the trpL mRNA progresses to the stop codon and ribosome pauses b. prevents 2 from h bonding with anything c. 3 h bonds with 4 and terminates transcription v. will turn operon off if there is an abundance of charged tRNAtrp 6. Transcriptional regulation in eukaryotes a. Prokaryotic vs. eukaryotic gene expression Prokaryotic Eukaryotic Control of transcription through specific Control of transcription through specific DNA-binding proteins DNA-binding proteins X Role played by chromatin structure Coordination achieved by operons X (aggregated transcriptional mechanisms into a few spots) X Differential splicing Attenuation X X Differential polyadenylation X Differential transport from nucleus to cytoplasm (membrane needed) Differential rates of translation Differential rates of translation (membrane needed) b. Structure of chromatin (Ch. 11) i. Nucleosomes ii. Solenoid iii. Chromatin fiber iv. Metaphase chromosome © Hannah Kennedy, Kent State University c. Chromatin modifications i. ATP-dependent chromatin remodeling = dynamic changes in the structure of chromatin that occur during the life of a cell; drives changes in the locations and composition of nucleosomes ii. Closed conformation = conformation of chromatin that makes transcription difficult or impossible iii. Open conformation = conformation of chromatin that makes it more accessible to transcription factors and RNA polymerase so transcription can happen Modification Whats Happening Alteration of DNA protein contacts - Sliding exposes DNA - Change in the relative positions of nucleosomes - Change in the spacing of nucleosomes over a large distance Alteration of the DNA path - DNA is pulled off nucleosome - Histone octamers are removed Remodeling of nucleosome core particle - Nucleosome dimer forms d. Cis-regulatory sequences i. Distal elements 1. Silencers = prevent transcription from occurring after binding a repressor 2. Enhancers = enhances the rate of transcription once bound by an activator ii. Proximal elements 1. Core promoters e. Assembly of transcription factors is required for the initiation of transcription i. 2 categories of TFs 1. general transcription factors = GTFs = required for the binding of RNA polymerase to the core promoter and its progression to the elongation stage; necessary for basal level transcription 2. regulator transcription factors = TFs that serve to regulate the rate of transcription of targen genes a. up regulation = phenomenon in which transcription is greatly increased b. down regulation = phenomenon in which transcription is decreased © Hannah Kennedy, Kent State University c. domains = regions within TFs that have specific function (e.g. DNA binding function/provide binding site for small effector molecule) d. motif = structure in which the domain or portion of it has a similar structure in many different proteins e. 2 protein complexes communicate effects of RTFs i. transcription factor IID = TFIID = a GTF that binds to the TATA box and is needed to recruit RNA polymerase to the core promoter; activator proteins enhance its ability to increase transcription ii. mediator = protein complex that mediates the interaction between RNA polymerase II and RTFs f. function is controlled in 3 ways i. binding of small effector molecules ii. protein-protein interactions iii. covalent modifications f. Alternative splicing = process in which certain pre-mRNAs can be spliced in more than 1 way to lead to polypeptides with different amino acid sequences i. The purpose: to allow a protein to be fine-tuned to function in a specific cell type ii. Why it’s important: gene regulation, efficiency, protein diversity iii. Constitutive exons = exons that are always found in the mature mRNA in all cell types iv. Alternative exons = exons that aren’t always found in mRNA after splicing; may change the function of a protein in a subtle way v. Splicing factors = play a key role in the splice sites (e.g. SR proteins); key effects is to modulate the ability of the spliceosome to choose 5’ and 3’ splice sites 1. Some act as repressors that inhibit ability of spliceosome to recognize splice site (exon skipping) 2. Some enhance ability of spliceosome to recognize specific splice sites 3. Alternative splicing occurs in different tissues bc each cell type has own concentration of splicing factors vi. Stability of mRNA is regulated by influencing the concentration of the mRNA (various factors contribute to the half-life) 1. Poly-A tail—the longer the tail the more stable the mRNA Ch. 23—Medical genetics and cancer 7. Concepts a. Cancer as genetic disease of somatic cells b. Role of cell cycle and how it is regulated c. Importance of fail-safe checkpoints during cell cycle 8. Characteristics common to all cancers a. Most cancers originate in a single cell that undergoes genetic changes that accumulate b. Benign growth forms that is followed by additional genetic changes c. Cancerous cells become malignant (3 characteristics of malignant cells) i. Cell division occurs in unregulated way ii. Cells are invasive = they invade healthy tissues iii. Cells are metastatic = can migrate to other parts of the body and cause other tumors 9. How we know that cancer/other diseases are genetic a. Observation of chromosol anomalies in cancer © Hannah Kennedy, Kent State University i. E.g. 9:22 translocation is responsible for Chronic Myeloid Leukemia ii. Chromosomes with different morphology in a karyotype is characteristic of cancer: missing chromosomes, chunks of chromosomes missing, etc. b. Families where risk of cancer is transmitted as a trait c. Carcinogens tend to be mutagens d. Individuals with DNA repair deficiencies that have an increased risk of cancer 10.Pedigrees a. Mode of inheritance: 2 questions to ask i. Autosomal or X-linked? 1. Autosomal is present in both sexes without any prevalent bias 2. X-liked appears from a mom to son inheritance pattern ii. Dominant or recessive? 1. Recessive isn’t present in every generation 2. Dominant doesn’t skip generations b. 5-10% of cancers involve germ-line mutations i. these are able to occur bc ppl inherited mutation from 1 or both parents that give them increased susceptibility to developing cancer c. predisposition for developing cancer is inherited in a dominant way i. actual development of cancer is recessive bc it relies on loss of function of gene d. loss of heterozygosity = LOH = the loss of function of a normal allele when the other allele was already inactivated 11.Cancer as a genetic disease a. Cancer = a disease characterized by uncontrolled proliferation of cells (i.e. normal fail-safe mechanisms that regulate cell growth and division have broken down) i. Progression of cellular growth that leads to cancer 1. Initial gene mutation converts normal cell to tumor cell 2. Tumor cell divides a lot to produce benign tumor 3. More genetic changes in the tumor cells lead to a malignant growth 4. Tumor cells invade surround tissues and some malignant cell metastasize by traveling through bloodstream to cause secondary tumors b. May start with cells that have a little different cell cycle (i.e. a little faster growth period than others)—progression may take decades i. Abnormal proliferation leads to crowing out of normal cells 12.Cell cycle is under genetic control a. Cell cycle is divided into i. Interphase 1. G1—first gap a. Period of a cells life when it becomes committed to divide b. Cell can accumulate molecular changes that cause it to progress through cycle (i.e. reaches the restriction point) c. Commitment to divide is based on several factors: i. Environmental conditions: sufficient nutrients ii. Signaling molecules to coordinate cell division 1. Growth factors = signaling molecules that promote cell division; help regulate the cell cycle by binding to cell surface receptors and initiate cascade to lead to division a. Ex = EGF = epidermal growth factor = secreted from endothelial cells and cause them to divide 2. S—synthesis of DNA 3. G2—second gap © Hannah Kennedy, Kent State University ii. Mitosis b. 3 checkpoints in the cell cycle Checkpoint What’s Happening G1/S - Size and DNA integrity is monitored - Checkpoint proteins (e.g. p53) can prevent formation of active cyclin/CDK complexes if DNA has damage G2/M - DNA synthesis and damage is monitored - Checkpoint proteins (e.g. p53) can prevent formation of active cyclin/CDK complexes if DNA has damage M - Spindle formation and attachment to kinetochores is monitored c. cyclins and CDKs are responsible for advancing a cell through the cell cycle i. ex = activated G1 cyclin/CDK complex is needed to advance the cell from the G1 phase to the S phase d. checkpoint failure may lead to genetic instability i. checkpoints allow damaged cells to repair themselves or to self-destruct ii. loss of checkpoint protein function can cause cancerous growth by unregulated cell division 13.Genomic changes and cancer a. Small-scale changes of genomes b. Large-scale changes i. E.g. colorectal cancer and visible chromosomal changes (can detect with PCR test) ii. E.g. mutant karyotype c. In-between scale changes 14.General properties of cancer (2 categories of genes that may be mutated or affected by cancer) a. Tumor suppressor genes i. Tumor suppressor genes = prevents cancerous growth; when inactivated by mutation, it becomes more likely that cancer will occur (loss of function mutation) 1. 2 categories of functions of TSGs a. genes that negatively regulate cell division (ex = Rb protein negatively regulates E2F) i. loss of function of negative regulator has direct effect on abnormal cell division rates b. genes that maintain genome integrity i. genome maintenance = cellular mechanisms that prevent mutations from occurring and/or prevent mutant cells from surviving or dividing (2 classes of proteins that are involved in this) 1. checkpoint proteins = proteins that detect genetic abnormalities like DNA breaks and improperly segregated chromosomes 2. proteins involved directly with DNA repair © Hannah Kennedy, Kent State University a. DNA repair enzymes; loss of one increases the chances that the cell will accumulate mutations that could make an oncogene or eliminate tumor-suppressor function 2. First ID’d in retinoblastoma a. Rb (retinoblastoma) protein is inactivated by CDK-Cyclin during G1/s checkpoint; tumor suppressor gene is found on the long arm of chromosome 13 i. Rb protein regulates E2F (a TF) that activates genes needed for cell cycle progression; binding of the 2 inhibits activity and prevents cell cycle progression 1. If both Rb gene copies are inactive, then E2F is always active and uncontrolled cell division happens b. Retinoblastoma protein regulates whether or not the cells will be growing so if it doesn’t work then the cells will keep growing unchecked and lead to retinoblastoma c. These individuals may be at risk of developing other cancers i. 2 hit-model: there are 2 copies of normal genes. Mutation occurs “first hit” and one gene is abnormal. There is still 1 functional gene at this point therefore we’re fine but not as protected. Second hit occurs, both genes become mutated, and growth will be uncontrolled. 1. Those with hereditary form already have 1 mutant gene from 1 parent so they only need 1 more mutation in the other tumor-suppressor gene copy to develop retinoblastoma 2. Those with non-inherited form of disease need 2 mutations in the same retinal cell ii. E.g. p-53 (transcription factor) critical for the DNA damage checkpoint by determining if a cell has DNA damage 1. In normal cells, p53 levels are low a. Mdm2 removes p53 from the nucleus and leads to its degradation by the proteasome b. acts as a negative regulator by interacting w GTFs to decrease the expression of other structural genes to inhibit the cell from dividing © Hannah Kennedy, Kent State University 2. In cells with DNA damage results in p53 phosphorylation and acetylation and activation of p53 as a transcription factor a. Mdm2 cannot bind to the modified p53 b. Inducing signal for the expression of the p53 gene is a ds DNA break 3. Once activated by DNA damage, p53 can employ 3 different pathways that prevent cell proliferation of those with DNA damage a. Cell tries to repair its DNA to prevent accumulation of mutations that activate oncogenes or inactive tumor suppressor genes b. If cell is in process of dividing, it can arrest itself in the cell cycle so it has more time to repair DNA and avoid producing 2 mutant daughter cells i. This is done by p53 stimulating the expression of p21 that inhibits the cyclin/CDK protein complexes that are needed to progress from G1 phase to S phase c. Apoptosis = programmed cell death i. Facilitated by caspases that digest cellular proteins iii. 3 common ways that a tumor-suppressor gene can be lose 1. mutation can occur specifically within a tumor-suppressor gene to inactivate function a. ex = mutation can inactivate promoter or introduce early stop codon that prevent expression of functional protein 2. DNA methylation: inhibits the transcription of genes when in vicinity of promoter 3. Aneuploidy: chromosome loss contributes to cancer progression bc the chromosome that was lost carried 1 or more tumor suppressor genes b. Proto-oncogenes i. Proto-oncogene = a normal, non-mutated gene that has the potential to become an oncogene 1. Oncogene = abnormally active gene that promotes cancerous growth (gain-of-function mutation occurs in the proto-oncogene and has 1 of 3 effects) a. amount of encoded protein is increased b. structural change in the encoded protein occurs that causes it to be overly active c. encoded protein is expressed in an inappropriate cell type ii. oncogenes encode protein that function in cell growth signaling pathways like growth factors, growth factor receptors, proteins in intracellular signaling pathways, and TFs 1. E.g. cyclins 2. Ex = c-myc is amplified in promyelocytic cell line; overexpression leads to transcriptional activation of genes that promote cell division © Hannah Kennedy, Kent State University 3. Ex = mutations that alter AA sequence of Ras protein cause functional abnormalities a. Decrease ability of Ras protein to hydrolyze GTP b. Increase rate of exchange of bound GDP for GTP i. Both result in greater amount of active GTP-bound form of Ras protein that keeps the signaling pathway on iii. 4 ways that proto-oncogenes are turned into oncogenes 1. missense mutations: change in AA sequence of can cause it to function in abnormal way a. ex = Ras protein changes a glycine to a valine 2. gene amplification (i.e. abnormal increase in the copy number of proto-oncogene): increases the amount of the encoded protein, leading to malignancy a. ex = c-myc gene in leukemia 3. chromosomal translocation: piece of chromosome can be translocated to another chromosome and affect the expression of genes at the breakpoint site a. ex = breakpoint in chromosome 8 causes overexpression of c- myc gene b. ex = 9:22 translocation is responsible for Chronic Myeloid Leukemia 4. viral integration: when virus integrates into chromosome it enhances the expression of close proto-oncogenes 15.Cancer susceptibility genes increase the risk of cancer (3 scenarios) a. Large number of genes are mutated in cancer cells that provide a type of growth advantage for the cell population from which cancer developed b. Abnormalities in chromosome structure and number are associated with caner i. If tumor suppressor genes were on missing chromosome then function is lost, too ii. If there are extra chromosomes and they have proto-oncogenes, then the expression of those genes can be overactive c. Tumor cells usually have chromosome that have translocations that can create fused genes or place 2 genes close together so that regulatory sequences of 1 affect expression of the other 16.Mutagens and carcinogens a. Carcinogen = an environmental agent that causes cancer b. Can conduct an Ames test to do this c. E.g. Benzopyrene d. Potential carcinogen—diet i. Red meat and colon cancer 1. High fat diets likely account for half of all tumors 17.Viruses may contribute to cancers a. Repeated viral integration disrupts chromosomes causing insertional mutagenesis (e.g. HIV, hepatitis B and predisposition to hepatocellular carcinoma) b. E.g. papilloma virus promotes cervical cancer by blocking tumor suppressors © Hannah Kennedy, Kent State University


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