1. DNA Week 2 1

2. DNA Review DNA Cell cycle Proteins Flow of information 2

3. DNA [deoxyribonucleic acid] The primary information-bearing molecule of life Proteins are made in accordance with the information encoded in DNA 3

4. Nucleic Acids A class of macromolecules that include DNA, RNA and ATP Nucleotides ◦ 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)] 4

5. Genome The complete collection of an organism's genetic information 5

6. 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 6

7. Chromosomes The 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 7

8. The cell cycle, cell division & DNA replication Cell division: approximately 25 million cell divisions take place per second! Cell division ◦ Necessary for growth, repair and replacement of dying cells DNA replication: the duplication of DNA before cell division Cell cycle: the repeating pattern of growth, genetic replication, and division 8

9. Proteins Greek: 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 9

10. The flow of information Central dogma DNA  RNA  Protein ◦ [gene expression: the process by which DNA directs the synthesis of proteins [and RNAs] 10

11. Gene Structure Two parts of a gene: ◦ Regulatory Region Coding Region 11

12. Gene Expression Transcription: 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)] 12

13. Gene Structure Promoter: 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 13

14. Gene Structure Coding region 14

15. Mutations The good, the bad, and the ugly 15

16. DNA Mutation: a permanent alteration in a DNA base sequence DNA 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 16

17. Note DNA 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] 17

18. The Good Most 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] 18

19. The Bad You might not make a particular protein 19

20. The Ugly Cancer! 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 20

21. Types of Mutations 21

22. Mutations Mutations in the promoter region and coding regions 22

23. Carcinogenic Agents Radiation Ionizing radiation Ultraviolet [UV] radiation Chemical Infectious pathogens Endogenous carcinogenic reactions 23

24. Carcinogenic Agents Radiation as a carcinogen ◦ Energy waves: gamma [  ], electromagnetic radiation, UV, X-rays ◦ Atomic particles: alpha [  ] and beta [  ] 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 24

25. Carcinogenic Agents Ultraviolet [UV] radiation ◦ UVA, UVB & UVC, with UVB being the most dangerous ◦ Pyrimidine dimers Skin 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 25

26. Carcinogenic Agents Chemical 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 26

27. Carcinogenic Agents Infectious pathogens as carcinogens ◦ Viruses [more about this in chapter 10] Endogenous carcinogenic reactions ◦ ROS [stop using oxygen!] 27

28. DNA Repair and Predispositions to Cancer This section is a bit too detailed for us, so we will review in general terms in class One-step repair Nucleotide excision repair (NER) Base excision repair Mismatch repair Recombinational repair 28

29. Conventional Therapies Chemotherapy and radiation therapy 29

30. Chemotherapy Goals: induce DNA damage and trigger apoptosis; interfere with DNA metabolism; alter cell division ◦ Alkylating agents and platinum-based drugs ◦ Antimetabolites ◦ Organic drugs 30

31. Radiation Therapy Generating ROS, DNA damage, and apoptosis 31

32. Heterogeneous cell sensitivity and drug resistance: obstacles to treatments 32