Ch. 19 – Gene regulation (and signal transduction)

1. Ch. 19 – Gene regulation (and signal transduction) Big Idea 3 – Essential Knowledge 3.B.1 and 2.A and 3.D

2. The main point of signal transduction? • We can receive a signal, which will activate a series of events which will eventually have an action

3. Vocabulary • Inducer – turns on the expression of specific genes • Repressor – inhibits the expression of specific genes • Regulatory proteins/regulatory sequences – control inducers and repressors

4. Overview: How Eukaryotic Genomes Work and Evolve • Two features of eukaryotic genomes are a major information-processing challenge: • First, the typical eukaryotic genome is much larger than that of a prokaryotic cell • Second, cell specialization (we have over 200 different types of cells) limits the expression of many genes to specific cells • The DNA-protein complex (what makes our chromosomes), called chromatin, is ordered into higher structural levels than the DNA-protein complex in prokaryotes

5. Chromatin structure is based on successive levels of DNA packing • Eukaryotic DNA is combined with a large amount of protein • Eukaryotic chromosomes contain an enormous amount of DNA relative to their condensed length • Each cell has over 6 feet of DNA inside it • If we spread out all of our DNA, it would stretch to the sun and back many times

6. Nucleosomes, or “Beads on a String” • Proteins called histones are responsible for the first level of DNA packing in chromatin • The association of DNA and histones seems to remain intact throughout the cell cycle • In electron micrographs, unfolded chromatin has the appearance of beads on a string

7. Gene expression can be regulated at any stage, but the key step is transcription (between DNA and mRNA) • All organisms must regulate which genes are expressed at any given time • A multicellular organism’s cells undergo cell differentiation (specialization in form and function)

8. Regulation of Chromatin Structure • Genes within highly packed heterochromatin (a type of chromatin that is tightly packed) are usually not expressed • It’s usually so tightly packed, it’s difficult for certain protein factors to access and find a place to bind • Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression • Chromatin-modifying enzymes provide initial control of gene expression by making a region of DNA either more or less able to bind the transcription machinery • This deals with epigenetics, and is outside the scope of the AP test (so don’t worry about the details)

9. Organization of a Typical Eukaryotic Gene • Associated with most eukaryotic genes are control elements (repressors, enhancers, etc), segments of noncoding DNA that help regulate transcription by binding certain proteins • Control elements and the proteins they bind are critical to the precise regulation of gene expression in different cell types

10. The Roles of Transcription Factors • To initiate transcription (changing DNA to mRNA), eukaryotic RNA polymerase (the enzyme that adds nucleotides to mRNA)requires the assistance of proteins called transcription factors • A transcription factor is a protein that binds to a specific DNA sequence and controls the flow of genetic info from DNA to mRNA • Can promote (with an activator) or block (repressor) the recruitment of RNA polymerase • (we’ll have examples at the end of the notes) • Generaltranscription factors are essential for the transcription of all protein-coding genes • In eukaryotes, high levels of transcription of particular genes depend on control elements interacting with specific transcription factors

11. Enhancers and Specific Transcription Factors • A promoter is a region of DNA that initiates transcription of a particular gene • Proximal control elements are located close to the promoter • Distal (away from the center) control elements, groups of which are called enhancers, may be far away from a gene or even in an intron (the part of the DNA that doesn’t code for a particular gene) • An activator is a protein that binds to an enhancer and stimulates transcription of a gene

12. Coordinately Controlled Genes • An operon is a unit of DNA containing a cluster of genes under the control of a single regulatory signal or promoter. • there are typically three components of an operon: a promoter, operator, and structural gene. • Unlike the genes of a prokaryotic operon, coordinately controlled eukaryotic genes each have a promoter and control elements • The same regulatory sequences (like stop) are common to all the genes of a group, enabling recognition by the same specific transcription factors

13. Cancer results from genetic changes that affect cell cycle control • The gene regulation systems that go wrong during cancer are the same systems that play important roles in embryonic development • Thus, research into the molecular basis of cancer has benefited from and informed many other fields of biology

14. Types of Genes Associated with Cancer • Mutations in two general types of genes lead to cancer: • Tumor-suppreser genes, which normally act like "brakes" to inhibit cell growth and division • Proto-oncogenes, which normally act like "gas pedals" to accelerate cell growth and division. • Mutations that inhibit the activity of tumor suppressor genes or that overactivate proto-oncogenes can drive cells to cancer; in either case, cells lose their brakes, hit the gas pedal, and accelerate uncontrollably toward a cancerous state. • A DNA change that makes a proto-oncogene excessively active converts it to an oncogene, which may promote excessive cell division and cancer

15. Tumor-Suppressor Genes • Tumor-suppressor genes encode proteins that inhibit abnormal cell division • Any decrease in the normal activity of a tumor-suppressor protein may contribute to cancer • Increased cell division, possibly leading to cancer, can result if the cell cycle is overstimulated or not inhibited when it normally would be

16. Cancer cont. • The p53 gene encodes a tumor-suppressor protein that is a specific transcription factor that promotes synthesis of cell cycle–inhibiting proteins • Named for its 53,000-dalton protein product, the p53 gene is often called the “guardian angel of the genome” • Mutations that knock out the p53 gene can lead to excessive cell growth and cancer

17. The Multistep Model of Cancer Development • More than one somatic mutation is generally needed to produce a full-fledged cancer cell • About a half dozen DNA changes must occur for a cell to become fully cancerous • These changes usually include at least one active oncogene and mutation or loss of several tumor-suppressor genes • Colorectal cancer, with 135,000 new cases and 60,000 deaths in the United States each year, illustrates a multistep cancer path

18. Colon LE 19-13 Loss of tumor- suppressor gene p53 Activation of ras oncogene Loss of tumor- suppressor gene APC (or other) Colon wall Loss of tumor- suppressor gene DCC Additional mutations Small benign growth (polyp) Larger benign growth (adenoma) Normal colon epithelial cells Malignant tumor (carcinoma)

19. Cancer cont. • Certain viruses promote cancer by integration of viral DNA into a cell’s genome • By this process, a retrovirus may donate an oncogene to the cell • Viruses seem to play a role in about 15% of human cancer cases worldwide • Ex – human pappillomavirus

20. Inherited Predisposition to Cancer • The fact that multiple genetic changes are required to produce a cancer cell helps explain the predispositions to cancer that run in some families • Individuals who inherit a mutant oncogene or tumor-suppressor allele have an increased risk of developing certain types of cancer • Offspring could inherit the mutation, or be more suseptible to acquiring it (ex – Angelina Jolie recently had a double masectomy because she inherited the BRCA1 or BRCA2 mutation, which means an increased risk for both breast and ovarian cancer.

21. The Relationship Between Genomic Composition and Organismal Complexity • Compared with prokaryotic genomes, the genomes of eukaryotes: • Generally are larger • Have longer genes • Contain much more noncoding DNA

22. Movement of Transposons and Retrotransposons • A transposable element is a DNA sequence that can change its position in the genome (can create or reverse a mutation) • Eukaryotic transposable elements are of two types: • Transposons, which move within a genome by means of a DNA intermediate • Retrotransposons, which move by means of an RNA intermediate

23. Duplication of Chromosome Sets • Accidents in meiosis can lead to one or more extra sets of chromosomes, a condition known as polyploidy • The genes in one or more of the extra sets can diverge by accumulating mutations; these variations may persist if the organism carrying them survives and reproduces • More common in plants (can cause sterility, so we like to have this in some cases)

24. Duplication and Divergence of DNA Segments • Unequal crossing over during prophase I of meiosis can result in one chromosome with a deletion and another with a duplication of a particular region

25. Overview of positive and negative control • Regulatory proteins can inhibit gene expression by binding to DNA and blocking transcription (negative control) • Regulatory proteins can stimulate gene expression by binding to DNA and stimulating transcription (positive control) – or binding to repressors to inactivate repressor function

26. Bozeman Biology Video – positive and negative • http://www.youtube.com/watch?v=3S3ZOmleAj0

27. Repressors and Gene Expression

28. The Lac Operon • (DNW)The following slides illustrate how the bacteria E. Coli turns its genes on and off • Operon – A group of genes that work together • (DNW) The Lac operon in E. Coli allows the bacteria to digest the sugar Lactose

29. Operator RNA Polymerase Genes that code for digestive enzymes Regulatory Gene Promotor DNA Repressor Repressor Repressor Repressor The regulatory gene codes for production of the repressor The repressor binds to the DNA which prevents RNA polymerase from binding to the promotor, which prevents the digestive enzymes from being made.

30. When lactose is present in the environment, the lactose binds to the repressors. What do you notice happens to the repressor when lactose binds to it? Repressor Lactose

31. Operator Genes that code for digestive enzymes Regulatory Gene Promotor RNA Polymerase Repressor Repressor Repressor Repressor

32. The new shape of the repressor does not fit into the repressor binding site. What does this mean? Repressor

33. Operator Genes that code for digestive enzymes Regulatory Gene Promotor RNA Polymerase Digestive Enzyme Repressor Digestive Enzyme

34. Digestive Enzyme Digestive Enzyme Lactose Lactose

35. Once the digestive enzymes have digested all of the lactose, the repressors return to their normal shape, and go back to the repressor binding site. Repressor Digestive Enzyme Lactose

36. When lactose is not present, the Repressors go back to their original shape and return to the operator on the DNA strand. The digestive enzymes are no longer made. What factor is responsible for the production of digestive enzymes? Repressor