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. Change base sequence 2. Add or remove nucleotide(s) 3
Examples Change base sequence Base substitution 5 CCCGCTAGATA 3 5 CCCGCGAGATA 3 3 GGGCGARCTAT 5 3 GGGCGCTCTAT 5 Add or remove a single base pair 5 GGCGCTAGATC 3 5 GGCAGCTAGATC 3 3 CCGCGATCTAG 5 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
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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
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 9
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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 11
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 12
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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 14
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 15
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 16
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Methyl-directed mismatch repair system Base mismatch is an abnormality where the AT/GC rule 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 18
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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 20
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 21
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 22
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 23
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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 25
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 26
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Proto-oncogene Normal gene that, if mutated, can become an oncogene 4 common genetic changes 1. Missense mutations 2. Gene amplifications 3. Chromosomal translocations 4. Retroviral insertions 28
Missense mutations Chemical mutagens have been shown to cause missense mutations leading to cancer 29
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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 31
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 32
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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 34