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10 Mutations in the P53 Gene, Changing in Cell Cycle Regulation and Apoptosis

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10 Mutations in the P53 Gene, Changing in Cell Cycle Regulation and Apoptosis Introductory biophysics A. Y. 2017-18 10. Mutations and carcinogenesis Edoardo Milotti Dipartimento di Fisica, Università di Trieste “DNA is by no means the inert substance that might be supposed from naive consideration of genome stability.” D. Voet and J. G. Voet, “Biochemistry, 4th ed.”, Wiley 2011 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Mutations Sometimes errors in DNA duplication or repair occur, giving rise to new nucleotide sequences: these errors are called mutations. Mutations can occur both in somatic or germ cells*. Mutations in somatic cells are not inherited and they can be neglected from an evolutionary point of view. However, mutations in somatic cells are also relevant because they can lead to disease and death. *Human cells are either somatic cells or germ cells.Germ cells are either a sperm or an egg, all other human cells are called somatic cells. Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Estimates of mutation rates (very difficult, only few estimates exist... this one is from Drake et al., “Rates of Spontaneous Mutation”, Genetics 148 (1998) 1667) mutation rate per mutation rate per base pair per effective genome per replication mutation rate replication per genome mutation rate per per replication effective effective genome genome genome size per sexual size generation Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 • single-base or point mutations affect a single nucleotide • substitution mutations substitute one base for another • transitions exchange two purines or two pyrimidines • transversions exchange one purine with one pyrimidine • insertions/deletions insert/delete one base in the sequence • segmental mutations are similar, but they affect two or more adjacent nucleotides Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Transitions and transversions Transitions: purine to purine or pyrimidine to pyrimidine Transversions: purine-pyrimidine exchange Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Hydrolytic deamination of cytosine (net result, C to T: a transition) Cytosine Uracil Uracil is analogous to thymine, and this reaction eventually converts the base pair C:G to T:A Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 DNA damage DNA can be damaged by • Genotoxic chemicals (exogenous damage) • Reactive species from cell metabolism (endogenous damage) • Viruses • Radiation Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 DNA Damage I: Base Alterations and Single-Strand Breaks • A base alteration occurs when additional bonds between atoms are formed or broken or new chemical groups attach to the base. All of those situations result in a modified base structure that must be repaired. • An abasic site occurs when a base separates from the sugar, leaving behind an unpaired base. • Single strand breaks in the phosphodiester backbone arise largely from hydroxyl radical attack at sugar units comprising the backbone. A gap opens in the normally intact DNA. All three of these general types of lesions are repaired with only a slight risk of genetic change. (adapted from R. J. Reynolds and J. A. Schecker, “Radiation, Cell Cycle, and Cancer”, Los Alamos Science, n. 23 (1995) p. 51) Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 DNA Damage II: Double-Strand Breaks Double-strand breaks result from two single-strand breaks that are induced at closely opposed positions in the complementary strands. • Simple double strand breaks (upper red box) can often be repaired by a simple end-joining procedure. • Ionizing radiation often induces a complex lesion (lower red box) with base alterations and base deletions accompanying the breaks. (adapted from R. J. Reynolds and J. A. Schecker, “Radiation, Cell Cycle, and Cancer”, Los Alamos Science, n. 23 (1995) p. 51) Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 from D. Voet and J. G. Voet, “Biochemistry, 4th ed.”, Wiley 2011 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Oxidative attack is activated by metabolites that occur naturally inside cells, or by ions that form in the water environment and that are due either to chemicals or to radiation (ROS = Reactive Oxygen Species). Globally this is called oxydative stress, and the damage associated to self-produced chemicals is called endogenous damage. Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Pyrimidine dimers (thymine dimers) from UV irradiation these covalent bonds reduce the base stackinG distance from 0.34 nm to 0.16 nm Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Pyrimidine dimers block the normal process of DNA copy. If left unrepaired they kill E. coli. In humans, DNA Polymerase η skips the defect and performs a copy past the damaged DNA section, albeit with reduced accuracy (10-2 – 10-3). Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 DNA repair Molecular mechanisms sense DNA damage, activate repair mechanisms, and stop the cell cycle progression if the cell is proliferating. DNA damage is sensed by the MRN complex (double strand breaks) or by RPA (single strand breaks), and this sensing activates a complex molecular network. Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 If the cell is proliferating, the network also stops the cell at some specific checkpoints Cell cycle checkpoints. (source: Geoffrey M. Cooper e Robert E. Hausman: “The Cell: A Molecular Approach. 5th ed.”, Sinauer Associates 2009.) Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 DNA damage, such as that resulting from irradiation, leads to rapid increases in p53 levels. The protein p53 then signals cell cycle arrest at the G1 checkpoint. (source: Geoffrey M. Cooper e Robert E. Hausman: “The Cell: A Molecular Approach. 5th ed.”, Sinauer Associates 2009.) Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Cell “Radiation, Schecker, A. J. and Reynolds J. R. from adapted 51 p. (1995) 23 n. Science, Alamos Los Cancer”, and Cycle, Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Mutations and cancer Broken mechanisms in tumor cells. From D. Hanahan and R. A. Weinberg, “Hallmarks of Cancer: The Next Generation”, Cell 144 (2011) 646 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 (2011)646 144 Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 fromHanahan D. and R. A. Weinberg, “Hallmarks of Cancer: The Next Cell Generation”, Gene modifications linked to cancer (from Vogelstein et al., Nature 408 (2000) 307) Oncogenes. These are analogous to the accelerators in a car. Oncogenes stimulate appropriate cell growth under normal conditions, as required for the continued turnover and replenishment of the skin, gastrointestinal tract and blood, for example. A mutation in an oncogene is tantamount to having a stuck accelerator: even when the driver releases his foot from the accelerator pedal, the car continues to move. Likewise, cells with mutant oncogenes continue to grow (or refuse to die) even when they are receiving no growth signals. Examples are Ras, activated in pancreatic and colon cancers, and Bcl-2, activated in lymphoid tumours. Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Gene modifications linked to cancer/ctd. (from Vogelstein et al., Nature 408 (2000) 307) Tumour-suppressor genes. When the accelerator is stuck to the floor, the driver can still stop the car by using the brakes. Cells have brakes, too, called tumour-suppressor genes. These keep cell numbers down, either by inhibiting progress through the cell cycle and thereby preventing cell birth, or by promoting programmed cell death (also called apoptosis). Just as a car has many brakes (the foot pedal, handbrake and ignition key), so too does each cell. When several of these brakes are rendered non-functional through mutation, the cell becomes malignant. Examples are the gene encoding the retinoblastoma protein, inactivated in retinoblastomas, p53, and p16INK4a, which inhibits cyclin-dependent kinases and is inactivated in many different tumours. Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Gene modifications linked to cancer/ctd. (from Vogelstein et al., Nature 408 (2000) 307) Repair genes. Unlike oncogenes and tumour-suppressor genes, repair genes do not control cell birth or death directly. They simply control the rate of mutation of all genes. When repair genes are mutated, cells acquire mutations in oncogenes and tumour-suppressor genes at an accelerated rate, driving the initiation and progression of tumours. In the car analogy, a defective repair gene is much like having a bad mechanic. Examples are nucleotide-excision- repair genes and mismatch-repair genes, whose inactivation leads to susceptibility to skin and colon tumours, respectively. Edoardo Milotti - Introductory biophysics - A.Y. 2017-18 Note: homeostasis in cells Homeostasis is the property of a system in which variables are regulated so that internal conditions remain stable and relatively constant. Examples of homeostasis include the regulation of temperature and the balance between acidity and alkalinity (pH). It is a process that maintains the stability of the human body's internal environment in response to changes in external conditions. Example: the levels of many
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