Main description:

This book is concerned with the genetic consequences of nu cleotide pool imbalance. There are a number of ways in which this state can be achieved and the majority of papers in this volume de scribe the effects of nucleotide pool imbalance on DNA replication and repair, and the induction of gene mutations in various organisms. This book grew out of a Conference on "Genetic Consequences of Nu cleotide Pool Imbalance" which was held at the National Institute of Environmental Health Sciences on May 9-11, 1983. The Organizing Com mittee consisted of Drs. Diana Anderson (BIBRA), Robert Haynes (York University), Bernard Kunz (NIEHS), Barry Glickman (NIEHS), and Frederick J. de Serres (NIEHS), Chairman. The meeting was org- ized by the staff of the Office of the Associate Director for Genetics and was financed solely by the National Institute of Environmental Health Sciences. Frederick J. de Serres, Ph.D. Associate Director for Genetics v CONTENTS SECTION I. INTRODUCTION Molecular Mechanisms in Genetic Stability and Change: 1 The Role of Deoxyribonucleotide Pool Balance ****** Robert H. Haynes SECTION II. NUCLEOTIDE METABOLISM 25 Metabolic Effects of Poly(ADP-ribose) Inhibitors ******** Kathryn M. Milam and James E. Cleaver Ribonucleotide Reductase and Deoxyribonucleotide 33 POQ 1 s ............................................ . Peter Reichard 47 Enzymatic Channeling of DNA Precursors ****************** Christopher K. Mathews A Possible Secondary Role for Thymine-Containing DNA 67 Precursors ....................................... . Robert J. Melamede and Susan S. Wallace Multiple Mechanisms of Adenosine Toxicity in an Adenosine Sensitive Mutant of Baby Hamster 103 Kidney (BHK) Cells ............................... .

Contents:

Section I. Introduction.- Molecular Mechanisms in Genetic Stability and Change: The Role of Deoxyribonucleotide Pool Balance.- Section II. Nucleotide Metabolism.- Metabolic Effects of Poly(ADP-ribose) Inhibitors.- Ribonucleotide Reductase and Deoxyribonucleotide Pools.- Enzymatic Channeling of DNA Precursors.- A Possible Secondary Role for Thymine-Containing DNA Precursors.- Multiple Mechanisms of Adenosine Toxicity in an Adenosine Sensitive Mutant of Baby Hamster Kidney (BHK) Cells.- Section III. DNA Replication Errors Caused by Nucelotide Imbalance.- Effects of Altered Nucleotide Concentrations on the Fidelity of DNA Replication.- Response of CHO Cell DNA Polymerase Alpha to dCTP and dTTP Pool Imbalance: Relation to DNA Synthesis Inhibition, Survival, and Mutation.- Misincorporation of Deoxyuridine in Human Cells: Consequences of Antifolate Exposure.- Effects of Nucleotide Pool Imbalances on the Excision Repair of Ultraviolet-Induced Damage in the DNA of Human Diploid Fibroblasts.- Effect of Variations in the Conditions of DNA Synthesis Upon the Accuracy of DNA Replication.- Section IV. Genetic Consequences of Nucleotide Pool Imbalances.- Thymineless Mutagenesis in Bacteria.- Genetic and Biochemical Effects of Thymidylate Stress in Yeast.- Biological Consequences of Guanine Starvation.- Thymineless Death and Genetic Events in Mammalian Cells.- Induction of Mitochondrial Mutations in Human Cells by Methotrexate.- Induction of Mutation and Chromosome Damage by Excess Bases and Nucleosides.- The Genetic Consequences of the Thy? Mutation to CHO Cells.- Deoxyribonucleoside-Induced Selective Modulation of Cytotoxicity and Mutagenesis.- Section V. Base Analog and Nucleotide Mutagenesis.- Viewing the Complexities of Mutagenesis from an Evolutionary Perspective.- Mutagenesis by Incorporation of Alkylated Nucleotides.- 2-Aminopurine Mutagenesis in Escherichia coli.- Mutagenicity of 2-Aminopurine, 6-N-Hydroxylaminopurine and 2-Amino-N6-Hydroxyadenine in Neurospora crassa.- Bromodeoxyuridine Mutagenesis and Deoxyribonucleotide Pool Imbalance in Mammalian Cells.- The Biochemical Basis of 5-Bromouracil - and 2-Aminopurine-Induced Mutagenesis.- Mutation Induction by Excess Deoxyribonucleotides in Saccharomyces cerevisiae.- The Effects of Pyrimidine Nucleotides on Alkylating Agent Induced Cytotoxicity and Spontaneous and Induced Mutation to Purine Analog Resistance in V79 Cells.- Section VI. Biological Implications of Nucleotide Pool Imbalances.- Aspects of DNA Repair and Nucleotide Pool Imbalance.- Agents Which Decrease Intracellular Thymidine Pools Cause an Augmentation in Human Natural Killer Activity in vitro.- Oncogenic Transformation of C3H/10T1/2 Cl 8 Mouse Embryo Fibroblasts by Inhibitors of Nucleotide Metabolism.- Regulation of Extracellular Thymidine Pools in Human Blood Samples.- Purine Nucleotide Imbalance in Immunodeficiency Disorders.- Contributors.