Porth's Essentials of Pathophysiology, 4e

88

Cell and Tissue Function

U N I T 1

division involved in gamete (i.e., ovum and sperm) for- mation, the fertilization process, and the mitotic cell divisions involved in the formation of a new organism from the single-celled fertilized ovum called the zygote . Although genes have gotten a lot of attention, it is the proteins that the genes encode that make up the major- ity of cellular structures and contribute to their func- tion. Proteins are responsible for the functional diversity of cells, they perform most biologic functions, and it is at their level that many regulatory processes take place, many disease processes occur, and most drug targets are found. The term proteome is a relatively new term, cre- ated to define the complete set of proteins encoded by a genome. Proteomics, the study of the proteome, uses highly sophisticated technologic methods to examine the molecular and biochemical events in a cell. DNA Structure and Function The DNA molecule that stores the genetic information in the nucleus is a long, double-stranded, helical structure. Deoxyribonucleic acid is composed of nucleotides , which consist of phosphoric acid, a five-carbon sugar called deoxyribose , and one of four nitrogenous bases. These nitrogenous bases carry the genetic information and are divided into two groups: the pyrimidine bases , thymine (T) and cytosine (C), which have one nitrogen ring; and the purine bases , adenine (A) and guanine (G), which have two. The backbone of DNA consists of alternating groups of sugar and phosphoric acid, with the paired bases pro- jecting inward from the sides of the sugar molecule. Double Helix and Base Pairing The native structure of DNA, as elucidated by James Watson and Frances Crick in 1953, is that of a spiral staircase, with the paired bases representing the steps (Fig. 5-1). A precise complementary pairing of purine and pyrimidine bases occurs in the double-stranded DNA molecule in which A is paired with T and G is paired with C. Each nucleotide in a pair is on one strand of the DNA molecule, with the bases on opposite DNA strands bound together by hydrogen bonds that are extremely stable under normal conditions. The double- stranded structure of DNA molecules allows them to replicate precisely by separation of the two strands, fol- lowed by synthesis of two new complementary strands. Similarly, the base complementary pairing allows for efficient and correct repair of damaged DNA molecules. Several hundred to almost 1 million base pairs can represent a gene, the size being proportional to the protein product it encodes. Of the two DNA strands, only one is used in transcribing the information for the cell’s protein-building machinery. The genetic informa- tion of one strand is meaningful and is used as a tem- plate for transcription; the complementary code of the other strand does not make sense and is ignored. Both strands, however, are involved in DNA duplica- tion. Before cell division, the two strands of the helix separate and a complementary molecule is duplicated

G A

C

T

G

C

A

T

G

C C

G

T

A

Replication fork

T

A

G

C

A

T

G

C

C

C

G

G

C

G

G

C

A

A

T

T

A

T T

T T

A

A

A

A

A

T

T

A

T

A

T

A T

A

A

A T

T

T

Parental strand

New strand

New strand

Parental strand

next to each original strand. Two strands become four strands. During mitotic cell division, the newly dupli- cated double-stranded molecules are separated and placed in each daughter cell by the mechanics of mitosis. As a result, each of the daughter cells again contains the meaningful strand and the complementary strand joined together as a double helix. In 1958, Meselson and Stahl characterized this replication of DNA as semiconserva- tive replication, as opposed to conservative replication, in which the parental strands reassociate when the two strands are brought together (Fig. 5-2). Although scientific discussion regarding the structure and functioning of a gene goes into explicit detail, it does not really address the question of what a gene is. Many scientists are now in agreement that the proteins encoded by DNA know no boundaries. This means that nucleo- tides from one part of the genome can combine with nucleotides from other regions at extreme distances on the DNA molecule. It is also proposed that the functions of some genes are controlled by regulatory regions, also at a distance. Moreover, researchers now recognize that many thousands of genes in the human genome do not code for protein assembly, but rather for segments of ribonucleic FIGURE 5-1. A replicating DNA helix.The parental strands separate at the replication fork. Each parental strand serves as a template for the synthesis of a new strand.The backbone of DNA consists of a sugar–phosphate backbone with paired pyrimidine bases (thymine [T] and cytosine [C] with their one nitrogen ring) and purine bases (adenine [A] and guanine [G] with their two nitrogen rings) projecting inward. (From Smith C, Marks AD, Lieberman M. Marks’ Basic Medical Biochemistry. 2nd ed. Philadelphia, PA: LippincottWilliams &Wilkins; 2005:222.)