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DNAWeek 2

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DNA ReviewDNACell cycleProteinsFlow of information

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DNA [deoxyribonucleic acid]The primary information-bearing

molecule of lifeProteins are made in accordance

with the information encoded in DNA

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Nucleic AcidsA class of macromolecules that

include DNA, RNA and ATPNucleotides

◦The building blocks of nucleic acids; they consist of a phosphate group, a sugar and a nitrogen-containing base [there are five major types of bases, usually designed by their first letter: Adenine, Thymine, Guanine, Cytosine, (& Uracil in RNA)]

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GenomeThe complete

collection of an organism's genetic information

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Genes:A segment of DNA

that may contain regulatory information and information for the synthesis of proteins◦ There are

approximately 25,000-30,000 genes in the human genome

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ChromosomesThe structural unit

containing most of an organism's genome

Consists of DNA and associated proteins [chromatin]

Human genome is made up of 23 pairs of chromosomes

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The cell cycle, cell division & DNA replicationCell division: approximately 25

million cell divisions take place per second! Cell division◦Necessary for growth, repair and

replacement of dying cellsDNA replication: the duplication

of DNA before cell divisionCell cycle: the repeating pattern

of growth, genetic replication, and division

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ProteinsGreek: proteion, "first‘”Class of macromolecules

composed of amino acids; many enzymes and hormones are proteins and proteins

Also involved in transport, protection, structure, storage and communication

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The flow of informationCentral dogmaDNA RNA Protein

◦[gene expression: the process by which DNA directs the synthesis of proteins [and RNAs]

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Gene StructureTwo parts of a

gene:◦ Regulatory Region

Coding Region

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Gene ExpressionTranscription: DNA mRNA [first

stage of protein synthesis]Translation: mRNA protein

[second stage of protein synthesis; "translating" from the language of nucleic acids (nucleotides) to the language of proteins (amino acids)]

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Gene StructurePromoter: a nucleotide sequence on DNA to

which RNA polymerase [RNAP] attaches prior to transcription of a gene [functions somewhat like the capital letter at the beginning of a sentence; the "starting line"]◦Recognition sequence: sequence recognized by

RNAP◦TATA box: sequence where DNA double helix

begins to separate◦Transcription factors: regulatory proteins that

assist in transcription ["handlers"] by mediating the binding of RNAP; more about these in chapter 3

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Gene Structure

Coding region

MutationsThe good, the

bad, and the ugly

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DNAMutation: a permanent alteration

in a DNA base sequenceDNA replication

◦Error rate during DNA replication: once in every 100,000 bases

◦Error rate at the end of DNA replication: one in every billion bases

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NoteDNA polymerases [DNAPS]: DNA

editing ["When first interpreting the ramifications of DNA and the genetic code...We totally missed the possible role of enzymes in repair...I later came to realize that DNA is so precious that probably many distinct repair mechanisms could exist." Francis H.C.Crick, molecular biologist, 1974, in The Biology of Cancer, by Robert A.Weinberg]

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The GoodMost mutations have no noticeable effect on

an organism and are the raw material of evolution [mutations create the variation that natural selection works on; e.g., to go from an organism with no eyes to one with eyes, there had to have been some mutations along the line that produced new proteins. "The capacity to blunder slightly is the real marvel of DNA. Without this special attribute, we would still be anaerobic bacteria and there would be no music." Lewis Thomas, biologist, 1979 in The Biology of Cancer, by Robert A. Weinberg]

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The BadYou might not make a particular

protein

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The UglyCancer! Example: in the skin cancer

melanoma, cells called melanocytes begin to divide out of control, often due to a point mutation [a mutation in a single base pair] in a gene called BRAF; a single change, an A had been substituted for a T at BRAF's 1,796th nucleotide, resulting in an altered protein that kept the cells moving through the cell cycle

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Types of Mutations

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MutationsMutations in the promoter region

and coding regions

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Carcinogenic AgentsRadiationIonizing radiationUltraviolet [UV] radiationChemicalInfectious pathogensEndogenous carcinogenic

reactions

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Carcinogenic AgentsRadiation as a carcinogen

◦Energy waves: gamma [g], electromagnetic radiation, UV, X-rays

◦Atomic particles: alpha [a] and beta [b]Ionizing radiation [alpha, beta and gamma

rays]◦ Ion: a charged particle (electrons and protons)

Reactive oxygen species [ROS]: interact of radiation with water [radiolysis], resulting in loss of electrons and highly reactive molecules [-OH, H2O2, & O-2 .]◦Role of antioxidants

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Carcinogenic AgentsUltraviolet [UV] radiation

◦UVA, UVB & UVC, with UVB being the most dangerous

◦Pyrimidine dimersSkin cancer

◦Squamous cell carcinoma [second most common, need to catch it early]

◦Basal cell carcinoma [least malignant, most common]

◦Melanoma [only 2-3% of skin cancers, but the most dangerous]

◦ABCDE rule

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Carcinogenic AgentsChemical carcinogens [we will

talk about this section in class, but for now, do not worry too much about this section]◦Polycyclic aromatic hydrocarbons

(PAHs)◦Aromatic amines◦Nitrosamines and nitrosamides◦Alkylating agents◦Fibrous minerals: asbestos and

erionite

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Carcinogenic AgentsInfectious pathogens as

carcinogens◦Viruses [more about this in chapter

10]Endogenous carcinogenic

reactions◦ROS [stop using oxygen!]

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DNA Repair and Predispositions to CancerThis section is a bit too detailed

for us, so we will review in general terms in class

One-step repairNucleotide excision repair (NER)Base excision repairMismatch repairRecombinational repair

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Conventional TherapiesChemotherapy and radiation

therapy

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ChemotherapyGoals: induce

DNA damage and trigger apoptosis; interfere with DNA metabolism; alter cell division◦ Alkylating agents

and platinum-based drugs

◦ Antimetabolites◦ Organic drugs

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Radiation TherapyGenerating ROS,

DNA damage, and apoptosis

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Heterogeneous cell sensitivity and drug resistance: obstacles to treatments