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Chapter 19 - Mammalian DNA Repair
- from SECTION 2 - MOLECULAR PATHOLOGY
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- By Alexio Capovilla, BSc (Hons), PhD, PDM, is a lecturer in the Division of Molecular Medicine and Haematology, University of the Witwatersrand, and is also employed as a senior research scientist by Elevation Biotech, a spin-out biotech company attached to the Division.
- Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
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- Book:
- Molecular Medicine for Clinicians
- Published by:
- Wits University Press
- Published online:
- 04 June 2019
- Print publication:
- 01 October 2008, pp 227-237
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- Chapter
- Export citation
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Summary
INTRODUCTION
This chapter provides a basic description of the major biochemical pathways that operate in mammalian cells to maintain the structure and integrity of genomic DNA. This is no trivial task for multicellular organisms, since, as we shall see, they are continually exposed to a plethora of agents that cause DNA damage. Failure to repair damaged DNA efficiently and consistently is incompatible with cellular life as we know it, and a large number of severe clinical disorders can now be attributed to defects in the cellular DNA repair machinery. We will look at examples of these in a little more detail below.
The importance of this vital function is further illustrated by the fact that DNA repair mechanisms are, for the large part, functionally conserved from primitive prokaryotes through to higher-order eukaryotes such as humans. Furthermore, at the time of writing (2006), over 150 gene products had been identified in humans that appear to have evolved primarily as either structural or catalytic components of DNA repair pathways, or gatekeepers of various stages of the cell cycle that are deliberately manipulated when DNA repair pathways are invoked. Readers are encouraged to consult an interesting web resource that has been constructed to describe the growing list of DNA repair genes at www.cgal.icnet.uk/ DNA_Repair_Genes.html
THE SPECTRUM OF DNA DAMAGE
For many years molecular biologists described DNA as a highly stable component of the cellular machinery that changes very little in structure or chemistry over time. The well established fact that DNA is the repository of coding information for all cellular life, and is responsible for the inheritance of this information from generation to generation, suggested that inherent physicochemical properties of DNA rendered it essentially chemically immutable. Recent evidence, however, has revealed a vastly different scenario, one in which all organisms are constantly exposed to a plethora of agents that cause significant structural and chemical changes in their DNA. Moreover, these changes are now known to occur through ongoing inter actions between DNA and by-products of normal cellular metabolism.
Chapter 7b - Protein Methods
- from Chapter 7 - Tools of Molecular Medicine
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- By Alexio Capovilla, BSc (Hons), PhD, PDM, is a lecturer in the Division of Molecular Medicine and Haematology, University of the Witwatersrand, and is also employed as a senior research scientist by Elevation Biotech, a spin-out biotech company attached to the Division.
- Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
-
- Book:
- Molecular Medicine for Clinicians
- Published by:
- Wits University Press
- Published online:
- 04 June 2019
- Print publication:
- 01 October 2008, pp 83-94
-
- Chapter
- Export citation
-
Summary
INTRODUCTION
In the post-genomic era, with sequencing of the entire human genome complete, there has been a great increase in our knowledge regarding the function of proteins encoded by the genome, the so-called proteome, and the role that aberrant protein expression and/or function plays in human disease pathogenesis. ‘Genomics’ refers to the comprehensive study of the function, interactions and dynamics of genes. In turn, ‘transcriptomics’, while having a similar objective, describes the function, interactions and dynamics of the genomic transcripts (i.e. mRNA, tRNA, rRNA and small RNAs such as miRNA and siRNA). ‘Proteomics’, by logical succession, describes the equivalent parameters for the complete set of proteins expressed by the genome through its transcripts. The entire set of proteins expressed by a particular cell/ organ ism constitutes its proteome. A number of variations on this theme are encountered increasingly in the literature. For instance, ‘metabolomics’refers specifically to the study of genes, transcripts and proteins involved in the regulation of metabolism.
In this chapter, we present a brief overview of some of the important tools that have been used to study the basic physicochemical properties of proteins, which have contributed significantly to developments in the field of proteomics. We also describe how these are increasingly being applied in the diagnosis and understanding of human disease.
PROTEIN BIOCHEMISTRY: BASIC CONCEPTS
The central dogma of molecular biology describes the process by which the genetic information contained within an organism's genes is translated into the functional components of life, proteins. This involves the produc tion of messenger RNA (mRNA) from the coding DNA sequence (transcription), which then serves as a template for protein synthesis (translation). In this manner, proteins are synthesised by polymerisation of the basic building blocks of all proteins, amino acids, in an order that is defined by the sequence of nucleotides in the coding DNA. It is the sequence in which these amino acids are incorporated into a protein molecule that is largely responsible for determining the threedimensional structure of the protein. This, in turn, is essentially what determines the biochemical activity of the protein and its role in the cell's life.