Porth's Essentials of Pathophysiology, 4e

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Genetic Control of Cell Function and Inheritance

C h a p t e r 5

Mitochondrial DNA In addition to nuclear DNA, part of the DNA of a cell resides in the mitochondria. Mitochondrial DNA (mtDNA) is inherited from the mother (i.e., matrilineal inheritance). It is a double-stranded closed circle contain- ing 37 genes, 24 of which are needed for mtDNA transla- tion and 13 of which are needed for oxidative metabolism. Replication of mtDNA depends on enzymes encoded by nuclear DNA. Thus, the protein-synthesizing apparatus and molecular components for oxidative metabolism are jointly derived from nuclear and mitochondrial genes. Genetic disorders of mtDNA, although rare, commonly affect tissues such as those of the neuromuscular system that have a high requirement for oxidative metabolism (see Chapter 6). From Genes to Proteins Although DNA determines the type of biochemical product that is needed by the cell and directs its synthe- sis, it is RNA, through the process of transcription and translation, which is responsible for the actual assembly of the products. RNA Structure and Function RNA, like DNA, is a large molecule made up of a long string of nucleotides. However, it differs from DNA in three aspects of its structure. First, RNA is a single-stranded rather than a double-stranded molecule. Second, the sugar in each nucleotide of RNA is ribose instead of deoxyribose. Third, the pyrimidine base thy- mine in DNA is replaced by uracil in RNA. Cells contain three types of RNA: messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). All three types of RNA are synthesized in the nucleus by RNA polymerase enzymes and then moved into the cytoplasm, where protein synthesis takes place. See Understanding DNA-Directed Protein Synthesis. Messenger RNA. Messenger RNA is the template for protein synthesis. It is a long molecule containing several hundred to several thousand nucleotides. Each group of three nucleotides forms a codon that is exactly comple- mentary to a nucleotide triplet of the DNA molecule. Messenger RNA is formed by a process called transcrip- tion . In this process, the weak hydrogen bonds of DNA are broken so that free RNA nucleotides can pair with their exposed DNA counterparts on the meaningful strand of the DNA molecule (see Fig. 5-1). As with the base pairing of the DNA strands, complementary RNA bases pair with the DNA bases. Ribosomal RNA. The ribosome is the physical structure in the cytoplasm where protein synthesis takes place. Ribosomal RNA forms 60% of the ribosome, with the remainder of the ribosome composed of the structural proteins and enzymes needed for protein synthesis. Unlike the two other types of RNA, rRNA is produced in a specialized nuclear structure called the nucleolus .

The formed rRNA combines with ribosomal proteins in the nucleus to produce the ribosome, which is then trans- ported into the cytoplasm. On reaching the cytoplasm, most ribosomes become attached to the endoplasmic reticulum and begin the task of protein synthesis. Transfer RNA. Transfer RNA is a clover-shaped mol- ecule containing only 80 nucleotides, making it the small- est RNA molecule. Its function is to deliver the activated form of an amino acid to the protein that is being syn- thesized in the ribosomes. At least 20 different types of tRNA are known, each of which recognizes and binds to only one type of amino acid. Each tRNA molecule has two recognition sites: the first is complementary for the mRNA codon, the second for the amino acid itself. Each type of tRNA carries its own specific amino acid to the ribosomes, where protein synthesis is taking place; there it recognizes the appropriate codon on the mRNA and deliv- ers the amino acid to the newly forming protein molecule. Transcription Transcription occurs in the cell nucleus and involves the synthesis of RNA from a DNA template (Fig. 5-4B). Genes are transcribed by enzymes called RNA polymer- ases that generate a single-stranded RNA identical in sequence (with the exception of U in place of T) to one of the strands of DNA. It is initiated by the assembly of a transcription complex composed of RNA polymerase and other associated factors. This complex binds to the double-stranded DNA at a specific site called the pro- moter region . Within the promoter region is the so-called “TATA box” that contains the crucial thymine-adenine- thymine-adenine sequence that RNA polymerase rec- ognizes and binds to, starting the replication process (Fig. 5-4A). The RNA polymerase continues to copy the meaningful DNA strand as it travels along the length of the gene, stopping only when it reaches a termination site with a stop codon. On reaching the stop signal, the RNA polymerase leaves the gene and releases the RNA strand. The RNA strand then is processed. Processing involves the addition of certain nucleic acids at the ends of the RNA strand and cutting and splic- ing of certain internal sequences. Splicing often involves the removal of stretches of RNA (Fig. 5-5). Because of the splicing process, the final mRNA sequence is dif- ferent from the original DNA template. The retained protein-coding regions of the mRNA sequences are called exons and the regions between exons are called introns . The functions of the introns are unknown. They are thought to be involved in the activation or deactiva- tion of genes during various stages of development. Splicing permits a cell to produce a variety of mRNA molecules from a single gene. By varying the splicing segments of the initial mRNA, different mRNA mol- ecules are formed. For example, in a muscle cell, the original tropomyosin mRNA is spliced in as many as 10 different ways, yielding distinctly different protein products. This permits different proteins to be expressed from a single gene and reduces the amount of DNA con- tained in the genome. ( text continues on page 93 )