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D:\My Documents\Wordperfect ANNEX F DNA repair and mutagenesis CONTENTS Page INTRODUCTION..................................................... 2 I. DNADAMAGEANDREPAIR...................................... 2 A. THEROLEOFDNAREPAIRGENESINCELLFUNCTION .......... 2 B. TYPESOFDAMAGEANDPATHWAYSOFREPAIR ............... 3 C. SUMMARY................................................. 8 II. REPAIRPROCESSESANDRADIOSENSITIVITY ...................... 9 A. RADIOSENSITIVITYINMAMMALIANCELLSANDHUMANS...... 9 1. The identification of radiosensitive cell lines and disorders ......... 9 2. Mechanisms of enhanced sensitivity in human disorders .......... 11 3. Analysis of genes determining radiosensitivity .................. 12 4. Summary ............................................. 17 B. RELATIONSHIP BETWEEN REPAIR AND OTHERCELLREGULATORYPROCESSES...................... 18 1. Radiosensitivity and defective recombination in the immune system: non-homologousendjoiningofDNAdouble-strandbreaks........ 18 2. Radiosensitivity and the cell cycle ........................... 21 3. Apoptosis:analternativetorepair?.......................... 23 4. Summary.............................................. 25 III. HUMAN RADIATION RESPONSES ................................. 26 A. CONTRIBUTION OF MUTANT GENES TOHUMANRADIOSENSITIVITY ............................. 26 B. INFLUENCEOFREPAIRONRADIATIONRESPONSES............ 29 C. SUMMARY................................................ 32 IV. MECHANISMSOFRADIATIONMUTAGENESIS ..................... 33 A. MUTATIONASAREPAIR-RELATEDRESPONSE................ 33 B. THESPECTRUMOFRADIATION-INDUCEDMUTATIONS......... 35 C. MOLECULAR ANALYSIS OF RADIATION-INDUCED MUTATIONS . 36 D. EFFECTOFRADIATIONQUALITY............................ 39 E. NOVEL MECHANISMS OF GENETIC CHANGE .................. 41 F. MUTATIONFREQUENCIESANDCONSEQUENCES.............. 44 G. SUMMARY................................................ 47 CONCLUSIONS..................................................... 47 References .......................................................... 49 2 ANNEX F: DNA REPAIR AND MUTAGENESIS INTRODUCTION 1. Risk estimates for the induction of human disease are 3. DNA repair is itself controlled by a specific set of obtained primarilyfrom epidemiological studies.Thesestudies genes encoding the enzymes that catalysecellular response can clearly distinguish radiation effects only at relatively high to DNA damage. Loss of repair function, or alteration of doses and dose rates. Togain information at lowdoses and low the control of repair processes, can have very serious dose rates, which are more relevant to typical human radiation consequencesfor cellsand individuals. It isanticipated that exposures, it is necessary to extrapolate the results of these DNA repair plays a critical role in protecting normal studies. To be valid, this extrapolation requires a detailed individuals from radiation effects, including cancer. understanding of the mechanisms by which radiation induces Clinical experience has revealed individuals who are both cancer and genetic disorders. hypersensitivetoradiation and cancer-prone; someofthese individuals have recently been shown to have defects in 2. Several lines of evidence show that sites of radiation- genes involved in the response to DNA damage. induced cell lethality, mutation, and malignant change are situated within the nucleus and that DNA is the primary 4. In recent years there have been significant advances target. When DNA is damaged by radiation, enzymes within in the molecular analysis of repair processes and the the cell nucleus attempt to repair that damage. The efficiency understanding of the mechanisms that induce genetic of the enzymatic repair processes determines the outcome: changes. Additionally, new methods have been developed most commonly, the structure of DNA is repaired correctly to simplify the identification of the genes involved. As the and cellular functions return to normal. If the repair is details of damage-repair processes become clearer, it is unsuccessful, incomplete, or imprecise, the cell may die or seen that these processes have considerable overlap with may suffer alteration and loss of genetic information (seen as other cellular control functions, such as those regulating mutation and chromosomal aberration). These information the cell cycle and immune defences. In this Annex the changes determine heritable genetic defects and are thought Committee continues to review such developments in to be important in the development of radiation-induced molecular radiobiology, as it began to do in Annex E, cancer. The more complete the knowledge of the ways in “Mechanisms of radiation carcinogenesis” of the which human cells respond to damage and of the mechanisms UNSCEAR 1993 Report [U3], in order to improve the underlying the formation of mutations and chromosomal understanding of how radiation effects are manifested in aberrations, the more accurate will be the predictions of the cells and organisms. oncogenic and hereditary effects of ionizing radiation. I. DNA DAMAGE AND REPAIR A. THEROLEOFDNAREPAIRGENES 6. Loss or alteration of information in a specific gene may IN CELL FUNCTION mean that none of that gene product (protein) is formed, or that the protein is less active, or that it is formed in an 5. The information needed to control cellular functions uncontrolled fashion (e.g. at the wrong time or in the wrong such as growth, division, and differentiation is carried by amount). While some minor genetic alterations may not affect the genes. Genes, which are specific sequences of DNA, act protein activity or interactions, others may significantly mainlythrough theproduction ofcomplementarymessages disrupt cellular function. Since certain proteins work in a (mRNA) that are translated into proteins. Proteins can number of different processes or complexes, the loss or have a structural role but commonlywork asenzymes, each impairment of one type of protein can affect several different of which catalyses a particular metabolic reaction. Thus functions of the cell and organism (pleiotropic effect). specific genes contain the code for (encode) specific cellular functions. The production of proteins can be timed 7. A verylarge number of genes, 60,000-70,000 [F14], are so that they work at specific points in the development of required to control the normal functions of mammalian cells a cell or organism, but protein function can also be and organisms. However, the genes form only a small part of controlled by post-translational modifications. These the genome (the complete DNA sequence of an organism), the modifications are carried out by other proteins, so that a remainder of which largely consists of many copies of complex set of interactions is necessary to fine-tune repetetive DNA sequence. The genes are linked in linear cellular functions. Proteins involved in important aspects arrays interspersed by non-coding sequences, to form of cell metabolism (e.g. DNA replication) may also work chromosomes located in the cell nucleus. Most genes are in multi-protein complexes [A1]. There is some evidence present in only two copies, each on a separate homologous also that some of the complexes are assembled into larger chromosome, one inherited from the mother and one from the structures situated in defined regions of the nucleus (e.g. father. To monitor damage and to maintain the genes without the nuclear matrix) [H2]. significant alteration is a major concern for the cell. Repair ANNEX F: DNA REPAIR AND MUTAGENESIS 3 processes are common to all organisms from bacteria to are arranged in two linear arrays (or strands) held together by humans and have evolved to correct errors made in replicating hydrogen bonds centrally and linked externally by covalent the genes and to restore damaged DNA. This fact has in bonds to sugar-phosphate residues (the DNA "backbone"). recent years provided a useful tool for molecular geneticists in The adenine base pairs naturally with thymine (A:T base the analysis of repair processes; well characterized micro- pair), while guanine pairs with cytosine (G:C base pair), so organisms can serve as model systems to understand the that one DNA strand has the complementary sequence of the structureandfunction ofrepair genes. Theinformation gained other. The sequence of the bases defines the genetic code; each in this way can sometimes also be used directly to isolate gene has a unique sequence, although certain common human genes of related function [L1]. While the structure and sequences exist in control and structural DNA elements. function of repair genes appears to be highly conserved from Damage to DNA may affect any one of its components, but it lower to higher organisms, the regulation of their activities is the loss or alteration of base sequence that has genetic may differ in different organisms. consequences. 8. The consequences of loss of repair capacity are seen in 12. Ionizing radiation deposits energy in tracks of a number of human syndromes and mutant cell lines. These ionizations from moving charged particles within cells, and showhypersensitivitytoenvironmental agents, and thehuman radiations of different quality may be arbitrarily divided into syndromes often have multiple symptoms, including cancer- sparsely ionizing, or low linear energy transfer (low-LET), proneness, neurological disorder, and immune dysfunction. and densely ionizing (high-LET). Each track of low-LET Good progress has been made over the last few years in radiations, such as x rays or gamma rays, consists of only
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