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MUTATION, DNA REPAIR AND CANCER 1 Mutation A heritable change in the genetic material Essential to the continuity of life Source of variation for natural selection New mutations are more likely to be harmful than beneficial DNA repair systems reverse DNA damage Cancer is a disease caused by gene mutations 2 Gene mutations alter the DNA sequence Point mutation affects only a single base pair 2 basic alterations 1. 2. Change base sequence Add or remove nucleotide(s) 3 Examples Change base sequence Base substitution 5’ – CCCGCTAGATA – 3’ → 3’ – GGGCGATCTAT – 5’ 5’ – CCCGCGAGATA – 3’ 3’ – GGGCGCTCTAT – 5’ Add or remove a single base pair 5’ – GGCGCTAGATC – 3’ 3’ – CCGCGATCTAG – 5’ → 5’ – GGCAGCTAGATC – 3’ 3’ – CCGTCGATCTAG – 5’ 4 Gene mutations may affect amino acid sequences Silent or neutral mutations Do not alter the amino acid sequence Genetic code is degenerate Missense mutation Changes a single amino acid in a polypeptide May be neutral if substituted amino acid similar in chemistry to original Sickle-cell anemia is the result of a single amino acid substitution 5 6 Nonsense mutation Change from a normal codon to a stop or termination codon Produces a truncated polypeptide Frameshift mutation Addition or deletion of nucleotides that are not multiples of 3 Completely different amino acid sequence downstream from mutation 7 Gene mutations outside of coding sequences Promoter Up promoter mutations or down promoter mutations Transcriptional response element/ operator site May alter regulation of transcription Splice junctions Mutations at the boundaries between introns and exons can prevent proper splicing Translational response elements May prevent proper translational regulation 8 The Lederbergs used replica plating to show that mutations are random events How do mutations occur? Result of pre-existing circumstances? Unplanned random events? Joshua and Ester Lederberg tested opposing views in bacteria using replica plating Only rare cells that had mutated survived selection Supported idea that mutations are random events Germ-line or somatic cell mutations Exact time and location of a mutation is critical to severity of effect and to the ability to pass on the mutation Germ-line cells give rise to gametes Can occur in a sperm or egg cell or in cell that gives rise to eggs and sperm Somatic cells are all other body cells Can occur early or late in development Genetic mosaic results from patches of mutated tissue 11 12 Spontaneous or induced mutations Spontaneous mutations result from abnormalities in biological processes Rates vary from species to species and from gene to gene Expected rate of background mutation approximately 1 mutation for every 1 million genes 13 14 Induced mutations are brought on by environmental agents Mutation rate higher than spontaneous mutation rate Mutagens are chemical or physical agents Can alter DNA in various ways 15 16 Mutagens Disrupt pairing by… Modifying nucleotide structure Nitrous acid deaminates bases so that modified bases do not pair with appropriate nucleotide Using base analogue similar to particular bases Alkylating bases Interfering with replication Acridine dyes insert between bases and distort the helix 17 18 Ionizing radiation has high energy and can penetrate deeply into biological materials to create free radicals X rays and gamma rays Base deletions, breaks in 1 or both DNA strands Nonionizing radiation has less energy and can only penetrate the surface UV rays can cause formation of thymine dimer causing gaps or incorporation of incorrect bases 19 20 Ames test Uses Salmonella typhimurium that cannot synthesize histidine due to a point mutation Bacteria cannot grow unless histidine added to medium OR mutation occurs allowing synthesis of histidine Test monitors rate at which second mutation occurs 21 22 DNA repair All living organisms must have the ability to repair changes that occur in DNA in order to minimize mutation Requires… DNA damage be detected Repair of DNA damage 23 Types of repair Direct repair Enzyme removes a modification (for example an alkyl group) Altered DNA strand removed and new segment synthesized More common Nucleotide excision repair Methyl-directed mismatch repair 24 Nucleotide Excision Repair (NER) Most common DNA repair system Region encompassing several nucleotides in the damaged strand is removed from the DNA Found in all eukaryotes. Intact undamaged strand is used as a template for resynthesis of a normal complementary strand 25 26 Methyl-directed mismatch repair system Base mismatch is an abnormality where the AT/GC rule is not obeyed DNA polymerase may make a mistake May correct itself with proofreading ability Methyl-directed mismatch repair systems exist in all species Detect mismatch and specifically remove segment from newly made strand Specifically repairs the new strand rather than the parental template strand 27 28 Cancer Disease of multicellular organisms that is characterized by uncontrolled cell division Over 1 million Americans are diagnosed with cancer each year, and about half that number will die from the disease In about 10% of cancers, a higher predisposition to develop the disease is an inherited trait Most cancers, about 90%, do not involve genetic changes that are passed from parent to offspring 29 Carcinogens About 80% of all human cancers are related to exposure to carcinogens Agents that increase the likelihood of developing cancer Most carcinogens, such as UV light and certain chemicals in cigarette smoke, are mutagens that promote genetic changes in somatic cells DNA alterations can lead to effects on gene expression that ultimately affect cell division, and thereby lead to cancer 30 Cancers originate from a single cell Mutates so that cell grows abnormally Tumor- an overgrowth of cells with no useful purpose Tumor may begin as a benign or precancerous 31 Cancerous stage Malignant - lost normal growth regulation Invasive- can invade healthy tissue Metastatic- can migrate to other parts of the body Left untreated, malignant cells will cause the death of the organism 32 33 Cancer-causing genes Oncogene When a mutation causes this gene to be overactive, uncontrolled cell growth occurs. Tumor-suppressor gene Normally, this gene encodes a protein that prevents cancer If a mutation eliminates this function, cancer can occur 34 Oncogenes Cell division regulated by hormones called growth factors Bind to cell surface and initiate cascade leading to cell division which includes activating specific genes Mutations in genes producing cell growth signaling proteins can change them into oncogenes producing abnormally high level of activity in some proteins An oncogene may promote cancer by keeping the cell division signaling pathway in a permanent “on” position In some cancers the amount of gene product is abnormally high In others the gene produces a functionally hyperactive protein 35 36 Proto-oncogene 1. 2. 3. 4. Normal gene that, if mutated, can become an oncogene 4 common genetic changes Missense mutations Gene amplifications Chromosomal translocations Retroviral insertions 37 Missense mutations Chemical mutagens have been shown to cause missense mutations leading to cancer 38 39 Gene amplifications Abnormal increase in copy number results in too much of the encoded protein Many human cancers are associated with the amplification of particular protooncogenes 40 Chromosomal translocations Two different chromosomes break, and the ends of the broken chromosomes fuse with each other incorrectly Very specific types of chromosomal translocations have been identified in certain types of tumors Chimeric genes are composed of two gene fragments fused together 41 42 Retroviral insertions Viral DNA may insert into a host chromosome in such a way that a viral promoter and response elements are next to a proto-oncogene May result in the overexpression of the proto-oncogene, thereby promoting cancer Alternatively, a virus may cause cancer because it carries an oncogene in the viral genome 43 Majority of cancers are caused by mutagens A few viruses are known to cause cancer in plants, animals, and humans Some viruses may cause cancer by modifying genes in the host cell Others carry oncogenes in the viral genome 44 Tumor-suppressor genes Role to prevent cancerous growth Proteins encoded by tumor-suppressor genes usually have one of two functions 1. Proteins that maintain the integrity of the genome by monitoring and/or repairing alterations in the genome 2. Checkpoint proteins check the integrity of the genome and prevent a cell from progressing past a certain point in the cell cycle Proteins that are negative regulators or inhibitors of cell division Their function is necessary to properly halt cell division otherwise cell division is abnormally accelerated 45 Checkpoint proteins Proteins called cyclins and cyclindependent protein kinases (cdks) are responsible for advancing a cell through the four phases of the cell cycle Formation of activated cyclin/cdk complexes can be stopped by checkpoint proteins p53 - about 50% of all human cancers are associated with defects in this gene 46 p53 is a G1 checkpoint protein Expression of the p53 gene is induced when DNA is damaged Then, a cell cannot progress from G1 to the S, or synthesis, phase of the cell cycle If DNA is repaired, a cell may later proceed through the cell cycle 47 Alternatively, if the DNA damage is too severe, the p53 protein will also activate other genes that promote programmed cell death or apoptosis Caspases function as proteases that digest selected cellular proteins causing the cell to break down It is beneficial for a multicellular organism to kill an occasional cell with cancer causing potential 48 When checkpoint genes are rendered inactive by mutation, the division of normal healthy cells may not be adversely affected For example, mice that are missing the p53 gene are born healthy Cell division leading to normal growth is regulated properly Checkpoint proteins such as p53 are not necessary for normal cell growth and division However, these mice are very sensitive to mutagens and easily develop cancer Loss of checkpoint protein function makes it more likely that undesirable genetic changes will occur that could cause cancerous growth 49 Rb gene Second example of a tumor-suppressor gene, which is a negative regulator of cell division First tumor-suppressor gene to be identified in humans by studying patients with a disease called retinoblastoma Some people have an inherited form that occurs early Other forms caused by environmental agents occur later in life 50 “Two-hit” model for retinoblastoma According to this idea, retinoblastoma requires two mutations to occur People have two copies of the Rb gene, one from each parent Individuals with the inherited form of the disease have one mutant gene from one of their parents They need only one additional mutation to develop the disease Likely to occur early in life People with the noninherited form of the disease must have two mutations in the same retinal cell to cause the disease Two rare events are far less likely than a single event, so the noninherited form of this disease is expected to 51 occur much later in life, and only rarely Rb protein negatively controls a regulatory transcription factor called E2F that activates genes required for cell cycle progression from G1 to S phase Binding of the Rb protein to E2F inhibits its activity and prevents cell division When both copies of Rb are defective, the E2F protein is always active resulting in uncontrolled cell division 52 Loss of tumor-suppressor gene function 3 common ways Mutation occurs specifically within a tumorsuppressor gene to inactivate its function Chromosome loss may contribute if the missing chromosome carries one or more tumor-suppressor genes Abnormal methylation of CpG islands near promoter regions 53 Cancer is a series of changes Cancer usually requires multiple genetic changes to the same cell Begin with a benign genetic alteration that, over time and with additional mutations, leads to malignancy Malignancy can continue to accumulate genetic changes that make it even more difficult to treat 54 Mutations in Approximately 300 Human Genes May Promote Cancer Not all of these mutant genes found in cancers have been directly shown to affect the growth rate of cells But such mutations are likely to be found in tumors because they provide some type of growth advantage for the cell population from which the cancer developed Over 1% of our genes have the potential to promote cancer if their function is altered by a mutation Lung cancer Diagnosed in approximately 170,000 men and women each year in the U.S. Worldwide, more than 1.2 million cases are diagnosed Nearly 90% of these cases are caused by smoking and are thus preventable Unlike other cancers for which early diagnosis is possible, lung cancer is usually detected only after it has become advanced and is difficult, if not impossible, to cure The five-year survival rate for lung cancer patients is less than 15% 56 Most are carcinomas Cancers of epithelial cells Mutations accumulate in basal cells and their numbers increase - hyperplasia As additional mutations accumulate, the basal cells develop more abnormal morphologies - dysplasia In the early stages, the abnormal basal cells are precancerous. If the source of chronic irritation (usually cigarette smoke) is eliminated, the abnormal cells are likely to disappear Alternatively, if smoking continues, these abnormal cells may accumulate additional genetic changes and lose the ability to stop dividing Such cells have become cancerous—the person has basal cell carcinoma Metastasis of these cells to other parts of the body will likely kill the patient, usually within a year of being diagnosed 57 58