The Cell - Aaron Kitcher PDF

The Cell Aaron kitcher  The cell is the basic unit of structure and function in the body. Many of the functions of cells are performed by particular subcellular structures PLASMA known as organelles. The plasma (cell) me...

The Cell Aaron kitcher  The cell is the basic unit of structure and function in the body. Many of the functions of cells are performed by particular subcellular structures PLASMA known as organelles. The plasma (cell) membrane allows selective MEMBRANE AND communication between the intracellular and extracellular compartments and aids cellular ASSOCIATED movement. Cells look so small and simple when viewed with the STRUCTURES ordinary (light) microscope that it is difficult to think of each as a living entity.. Equally impressive is that the physiology of our organs and systems derives from the complex functions of the cells they are composed. Complexity of function demands complexity of structure, even at the subcellular level. As the basic functional unit of the body, each cell is a highly organised molecular factory. Cells come in a wide variety of shapes and sizes. This great diversity, which is also apparent in the subcellular structures within different cells, reflects the diversity of function of other cells in the body. All cells, however, share specific characteristics; for example, they are all surrounded by a plasma membrane. For descriptive purposes, a cell can be divided into three principal parts: 1. Plasma (cell) membrane. The selectively permeable plasma membrane surrounds the cell, gives it form, and separates the cell’s internal structures from the extracellular environment. The plasma membrane also participates in intercellular communication. 2. Cytoplasm and organelles. The cytoplasm is the aqueous content of a cell inside the plasma membrane but outside the nucleus. Organelles (excluding the nucleus) are subcellular structures within the cytoplasm that perform specific functions. The term cytosol is frequently used to describe the fluid portion of the cytoplasm—that is, the part that cannot be removed by centrifugation. 3. Nucleus. The nucleus is a large, generally spheroid body within a cell. The largest organelles contain the DNA, or genetic material, of the cell and thus direct the cell’s activities. The nucleus also contains one or more nucleoli. Nucleoli are centres for the production of ribosomes, which are the sites of protein synthesis. Structure of the Plasma Membrane Because the intracellular and extracellular environments (or “compartments”) are aqueous, a barrier must be present to prevent the loss of enzymes, nucleotides, and other water-soluble cellular molecules. This barrier surrounding the cell cannot be composed of water-soluble molecules; it is instead composed of lipids. The plasma membrane (also called the cell membrane) and all of the membranes surrounding organelles within the cell are composed primarily of phospholipids and proteins. Phospholipids are polar (and hydrophilic) in the region that contains the phosphate group and nonpolar (and hydrophobic) throughout the rest of the molecule. Since the environment on each side of the membrane is aqueous, the hydrophobic parts of the molecules “huddle together” in the centre of the membrane, leaving the polar regions exposed to water on both surfaces. This results in a double layer of phospholipids in the cell membrane. The hydrophobic middle of the membrane restricts the passage of water and water-soluble molecules and ions. Certain of these polar compounds, however, do pass through the membrane. The membrane's specialised functions and selective transport properties are likely due to its protein content. Membrane proteins are described as peripheral or integral. Peripheral proteins are only partially embedded in one face of the membrane, whereas integral proteins span the membrane from one side to the other. Because the membrane is not solid— phospholipids and proteins are free to move laterally—the proteins within the phospholipid “sea” are not uniformly distributed. Instead, they present a constantly changing mosaic pattern, an arrangement known as the fluid-mosaic model of membrane structure. The proteins in the plasma membrane serve various functions, including structural support, transport of molecules across the membrane, and enzymatic control of chemical reactions at the cell surface. Some proteins function as receptors for hormones and other regulatory molecules that arrive at the membrane's outer surface. Receptor proteins are usually specific for one messenger, like an enzyme specific for a single substrate. Other cellular proteins serve as “markers” (antigens) that identify the tissue type of an individual. In addition to lipids and proteins, the plasma membrane contains carbohydrates, primarily attached to the membrane’s outer surface as glycoproteins and glycolipids. Specific glycolipids on the plasma membrane of red blood cells serve as antigens that determine the blood type.  The plasma membrane contains cholesterol, which accounts for 20% to 25% of the total lipid content of the membrane. The cells in the body with the highest cholesterol content are the Schwann cells, which form insulating layers by CLINICAL wrapping around certain nerve fibres. Their high cholesterol content is believed to be important in this insulating function. The ratio of APPLICATION cholesterol to phospholipids also helps determine a plasma membrane’s flexibility. When there is an inherited defect in this ratio, the flexibility of the cell may be reduced. This could result, for example, in the inability of red blood cells to flex at the middle when passing through narrow blood channels, thereby causing occlusion of these small vessels. Phagocytosis Most molecules and ions movement between the intracellular and extracellular compartments involves passage through the plasma membrane. However, the plasma membrane also participates in bulk transporting more significant portions of the extracellular environment. Bulk transport includes the processes of phagocytosis and endocytosis. White blood cells, known as neutrophils and connective tissue cells called macrophages (literally, “big eaters”) can perform amoeboid movement (move like an amoeba, a single-celled animal). This involves extending parts of their cytoplasm to form pseudopods (false feet), which pull the cell through the extracellular matrix—generally, an extra-cellular gel of proteins and carbohydrates. This process depends on the bonding of integrins, which span the plasma membrane of these cells, with proteins in the extracellular matrix. The ingested particle is now contained in an organelle called a food vacuole within the cell. The food vacuole will subsequently fuse with an organelle called a lysosome, and lysosomal enzymes will digest the particle. Phagocytosis, largely by neutrophils and macrophages, is an important immune process that defends the body and promotes inflammation. Phagocytosis by macrophages is also needed to remove senescent (aged) cells and those that die by apoptosis. Phagocytes recognise “eat me” signals—primarily phosphatidylserine—on the plasma membrane surface of dying cells. Apoptosis is a normal, ongoing activity in the body and is not accompanied by inflammation. Endocytosis Endocytosis is when the plasma membrane furrows inward instead of extending outward with pseudopods. One form of endocytosis, pinocytosis, is a nonspecific process performed by many cells. Pinocytosis allows a cell to engulf large molecules, such as proteins, and any other molecules that may be present in the extracellular fluid. Exocytosis Exocytosis is a process by which cellular products are secreted into the extracellular environment. Proteins and other molecules produced within the cell destined for export (secretion) are packaged within vesicles by an organelle known as the Golgi complex. In the process of exocytosis, these secretory vesicles fuse with the plasma membrane and release their contents into the extracellular environment. When the vesicle containing the secretory products of the cell fuses with the plasma membrane during exocytosis, the total surface area of the plasma membrane is increased. This process replaces material that was lost from the plasma membrane during endocytosis. Cilia and Flagella Cilia are tiny hairlike structures that project from the surface of a cell into the extracellular fluid. Motile cilia (those able to move) can beat like rowers in a boat, stroking in unison. Such motile cilia are found in only particular locations in the human body, where they project from the apical surface of epithelial cells (the surface facing the lumen or cavity) that are stationary and line specific hollow organs. For example, ciliated epithelial cells are found in the respiratory system and the female reproductive tract. In the respiratory airways, the cilia transport strands of mucus to the pharynx (throat), where the mucus can be swallowed or expectorated. In the female reproductive tract, the beating of cilia on the epithelial lining of the uterine tube draws the ovum (egg) into the tube and moves it toward the uterus. Sperm cells are the only cells in the body that have flagella. The flagellum is a single, whiplike structure that propels the sperm through its environment. Microvilli In areas of the body that are specialised for rapid diffusion, the surface area of the cell membranes may be increased by numerous folds called microvilli. The rapid passage of the products of digestion across the epithelial membranes in the intestine, for example, is aided by these structural adaptations. The surface area of the apical membranes (the part facing the lumen) in the intestine is increased by the numerous tiny fingerlike projections. Similar microvilli are found in the epithelium of the kidney tubule, which must reabsorb various molecules that are filtered out of the blood Cytoplasm and Cytoskeleton The material within a cell is known as cytoplasm. The cytoplasm contains structures called organelles that are visible under the microscope and the fluid-like cytosol that surrounds the organelles. When viewed in a microscope, the cytoplasm appears uniform and unstructured. However, the cytosol is not a homogeneous solution. It is a highly organised structure in which protein fibres—microtubules and microfilaments—are arranged in a complex latticework surrounding the membrane-bound organelles. The interconnected microfilaments and microtubules are believed to provide structural organisation for cytoplasmic enzymes and support various organelles. The cytoskeleton forms an amazingly complex “railway” system in a cell, on which large organelles (such as the nucleus), smaller membranous organelles (such as vesicles), and large molecules (including certain proteins and messenger RNA) travel to different and specific destinations. CELL MEMBRANE & TRANSPORT The cell membrane How Substances Cross Cell Membranes: Membrane controls the flow of materials in/out of the cell Either passive or active processes: Osmosis The passive transport of water across a selectively permeable membrane o Survival of the cell is dependent on osmoregulation o Water will flow from the hypotonic solution to the hypertonic solution through the lipid bilayer to form an isotonic solution Osmosis Osmosis Active Processes: - Transports substances against their concentration gradient - Transports substances that would otherwise be too large for channel proteins Active Transport (via carrier proteins): o (using energy –ATP- to move molecules across a membrane) o Similar to passive facilitated diffusion in that it requires carrier proteins o Active transporters (solute pumps) differ from facilitated diffusion in that they move solutes (mostly ions – Na+, K+, and Ca2+) uphill against their concentration gradients o In so doing, ATP is expended 2 Classes: Primary & Secondary Active Transport ▪ Distinguished according to their source of energy Primary Active Transporters: Energy comes directly from the hydrolysis of ATP Solute binds to the active site – then the protein is phosphorylated, causing it to change its shape and release the solute onto the other side of the membrane Eg: The Sodium Potassium Pump (The Na+/K+ - ATP ase Enzyme) o An Antiporter: 2 solutes opposite directions→ both against concentration gradients 1. Cytoplasmic Na+ binds to the protein, stimulating phosphorylation by ATP 2. Phosphorylation causes protein shape to change 3. Change in shape releases Na+ to the outside 4. K+ then binds to the protein, triggering the release of the phosphate group 5. Loss of phosphate restores protein to original shape 6. K+ ions are then released into the cell 7. Cycle then repeats Secondary Active Transporters Symporters: Using the potential energy of the concentration gradient created by a primary transporter, the high-concentration solute flows downhill, dragging with it another chemical Eg: Na+- Glucose Symporter Active Transport Via Vesicles: o Transport of large particles, macromolecules and fluids through cell membranes o Exocytosis: Vesicular transport of substances out of a cell (secretion) o Endocytosis: Vesicular transport of substances into a cell ▪ Phagocytosis: a large external particle is engulfed and enclosed in a vesicle (eg: in white blood cells) ▪ Pinocytosis: external fluid droplet (containing small solutes) is engulfed and enclosed in a vesicle (absorptive cells – eg: kidney & intestine) ▪ Receptor-Mediated: selective endocytosis – substance binds to membrane receptors & then enclosed in a vesicle Three Forms of Endocytosis Endocytosis is a form of active transport in which a cell envelopes extracellular materials. using its cell membrane. (a) In phagocytosis, which is relatively nonselective, the cell takes in a large particle. (b) In pinocytosis, the cell takes in small particles in fluid. (c) In contrast, receptor-mediated endocytosis is quite selective. When external receptors bind a specific ligand, the cell responds by endocytosing the ligand. Lysosomes After a phagocytic cell has engulfed the proteins, polysaccharides, and lipids in a particle of “food” (such as a bacterium), these molecules are kept isolated from the cytoplasm by the membranes surrounding the food vacuole. The large molecules of proteins, polysaccharides, and lipids must first be digested into their smaller subunits (including amino acids, monosaccharides, and fatty acids) before crossing the vacuole membrane and entering the cytoplasm. The digestive enzymes of a cell are isolated from the cytoplasm and concentrated within the membrane-bound organelles called lysosomes, which contain more than 60 different enzymes. A primary lysosome is one that has only digestive enzymes (about 40 different types) within an environment that is more acidic than the surrounding cytoplasm. A primary lysosome may fuse with a food vacuole (or with another cellular organelle) to form a secondary lysosome in which worn-out organelles and the products of phagocytosis can be digested. Thus, a secondary lysosome contains partially digested remnants of other organelles and ingested organic material. A lysosome that contains undigested wastes is called a residual body. Residual bodies may eliminate their waste by exocytosis, or the wastes may accumulate within the cell as the cell ages. Mitochondria All cells in the body, except mature red blood cells, have from a hundred to a few thousand organelles called mitochondria (singular, mitochondrion). Mitochondria serve as sites for the production of most of the energy of cells. Mitochondria vary in size and shape but have the same basic structure (fig. below). Each mitochondrion is surrounded by an inner and outer membrane, separated by a narrow inter-membranous space. The outer mitochondrial membrane is smooth, but the inner membrane is characterised by many folds called cristae, which project like shelves into the mitochondrion’s central area (or matrix). The cristae and the matrix compartmentalise the space within the mitochondrion and have different roles in generating cellular energy. Mitochondria can migrate through the cytoplasm of a cell and can reproduce themselves. Indeed, mitochondria contain their DNA. All of the mitochondria in a person’s body are derived from those inherited from the mother’s fertilised egg cell. Thus, a person’s mitochondrial genes are inherited from the mother. Mitochondrial DNA is more primitive (consisting of a circular, relatively small, double- stranded molecule) than found within the cell nucleus. Many scientists believe that mitochondria evolved from separate organisms, related to bacteria, that invaded the ancestors of animal cells and remained in a state of symbiosis. This symbiosis might not always benefit the host; for example, mitochondria produce superoxide radicals that can provoke oxidative stress and some scientists believe that accumulations of mutations in mitochondrial DNA may contribute to aging. Ribosomes Ribosomes are often called the “protein factories” of the cell because it is here that proteins are produced according to the genetic information contained in messenger RNA. The ribosomes are quite tiny, about 25 nanometers in size, and can be found both free in the cyto- plasm and located on the surface of an organelle called the endoplasmic reticulum (discussed next). Endoplasmic Reticulum Most cells contain a system of membranes known as the endoplasmic reticulum, or ER. The ER may be either of two types: (1) a granular, or rough, endoplasmic reticulum or (2) an agranular, or smooth, endoplasmic reticulum. A granular endoplasmic reticulum bears ribosomes on its surface, whereas an agranular endoplasmic reticulum does not. (3) The agranular endoplasmic reticulum serves various purposes in different cells; it provides a site for enzyme reactions in steroid hormone production and inactivation, for example, and a site for storing Ca2+ in striated muscle cells. The granular endoplasmic reticulum is abundant in protein synthesis and secretion cells, such as those of many exocrine and endocrine glands. Golgi Complex The Golgi complex called the Golgi apparatus, consists of several flattened sacs. This is like a stack of pancakes, but the Golgi sac “pancakes” are hollow, with cavities called cisternae within each sac. One side of the stack faces the endoplasmic reticulum and serves as a site of entry for vesicles from the endoplasmic reticulum that contain cellular products. The other side of the stack faces the plasma membrane, and the cellular products somehow get transferred to that side. This may be because the products are passed from one sac to the next, probably in vesicles, until they reach the sac facing the plasma membrane. Alternatively, the sac that receives the products from the endoplasmic reticulum may move through the stack until it reaches the other side. CELL NUCLEUS Most cells in the body have a single nucleus. Exceptions include skeletal muscle cells, which have many nuclei, and mature red blood cells, which have none. The nucleus is enclosed by two membranes—an inner and outer membrane called the nuclear envelope. The outer membrane is continuous with the endoplasmic reticulum in the cytoplasm. At various points, the inner and outer membranes are fused together by structures called nuclear pore complexes. These structures function as rivets, holding the two membranes together. Each nuclear pore complex has a central opening, the nuclear pore , surrounded by interconnected rings and columns of proteins. Small molecules may pass through the complexes by diffusion, but movement of protein and RNA through the nuclear pores is a selective, energy-requiring process that requires transport proteins to ferry their cargo into and out of the nucleus. Transport of specific proteins from the cytoplasm into the nucleus through the nuclear pores may serve a variety of functions, including regulation of gene expression by hormones. Transport of RNA out of the nucleus, where it is formed, is required for gene expression. Genes are DNA regions within the nucleus. Each gene contains the code for producing a type of RNA called messenger RNA (mRNA). As an mRNA molecule is transported through the nuclear pore, it becomes associated with either ribosomes free in the cytoplasm or with the granular endoplasmic reticulum. The mRNA then provides the code for the production of a specific type of protein. The primary structure of the protein (its amino acid sequence) is determined by the sequence of bases in mRNA. The base sequence of mRNA has been previously determined by the sequence of bases in the region of the DNA (the gene) that codes for the mRNA. Genetic expression therefore occurs in two stages: first genetic transcription (synthesis of RNA) and then genetic translation (synthesis of protein). Each nucleus contains one or more dark areas. These regions, which are not surrounded by membranes, are called nucleoli. The DNA within the nucleoli includes the genes that code for ribosomal RNA (rRNA) production.  Genome and Proteome The term genome can refer to all of the genes in a particular individual or all of the genes in a particular species. From information gained by the Human Genome Project, scientists currently believe that a person has approximately 25,000 different genes. Genes are regions of DNA that code (through RNA) for polypeptide chains. Until recently, it was believed that one gene coded for one protein, or at least one polypeptide chain recall that some proteins consist of two or more polypeptide chains. However, each cell produces well over 100,000 different proteins, so the number of proteins greatly exceeds the number of genes. The term proteome has been coined to refer to all of the proteins produced by the genome. This concept is complicated because, in a given cell, some portion of the genome is inactive. There are proteins produced by a neuron that are not produced by a liver cell, and vice versa. Further, a given cell will produce different proteins at different times, as a result of signaling by hormones and other regulators. The structure of chromatin. Part of the DNA is wound around complexes of histone proteins, forming particles known as nucleosomes. CLINICAL APPLICATION It is estimated that only about 300 genes out of a total of about 25,000 are active in any given cell. This is because each cell becomes specialized for particular functions in a differentiation process. The differentiated cells of an adult are derived, or “stem from,” those of the embryo. Embryonic stem cells can become any cell in the body—they are said to be pluripotent. The chromatin in embryonic stem cells is mostly euchromatin, with an open structure that permits its genes to be expressed. As development proceeds, more condensed regions of heterochromatin appear as genes become silenced during differentiation. Adult stem cells can differentiate into a range of specific cell types, but are not normally pluripotent. For example, the bone marrow of an adult contains such stem cells. These include hematopoietic stem cells, which can form the blood cells, and mesenchymal stem cells, which can differentiate into osteocytes (bone cells), chondrocytes (cartilage cells), adipocytes (fat cells), and other derivatives of mesoderm. Neural stem cells have been identified in the adult nervous system. These can migrate to particular locations and differentiate into specific neuron and glial cell types in these locations. RNA Synthesis Each gene is a stretch of DNA that is several thousand nucleotide pairs long. The DNA in a human cell contains over 3 billion base pairs—enough to code for at least 3 million proteins. Because the average human cell contains fewer proteins than this (30,000 to 150,000 different proteins), only a fraction of the DNA in each cell is used to code for proteins. Some of the DNA may be inactive or redundant, and some serve to regulate those regions that do code for proteins. For the genetic code to be translated into the synthesis of specific proteins, the DNA code first must be copied onto a strand of RNA. This is accomplished by DNA-directed RNA synthesis—the process of genetic transcription. There are base sequences for “start” and “stop,” and regions of DNA that function as promoters of gene transcription. Many regulatory molecules, such as some hormones, act as transcription factors by binding to the promoter region of a specific gene and stimulating genetic transcription. Transcription (RNA synthesis) requires the enzyme RNA polymerase, which engages with a promoter region to transcribe an individual gene. This pairing of bases, like that which occurs in DNA replication, follows the law of complementary base pairing: guanine bonds with cytosine (and vice versa), and adenine bonds with uracil (because uracil in RNA is equivalent to thymine in DNA). Unlike DNA replication, however, only one of the two freed strands of DNA serves as a guide for RNA synthesis. Once an RNA molecule has been produced, it detaches from the DNA strand on which it was formed. This process can continue indefinitely, producing many thousands of RNA copies of the DNA strand that is being transcribed. When the gene is no longer to be transcribed, the separated DNA strands can then go back together again. Types of RNA There are four types of RNA required for gene expression: (1) precursor messenger RNA (pre-mRNA), which is altered within the nucleus to form mRNA; (2) messenger RNA (mRNA), which contains the code for the synthesis of specific proteins; (3) transfer RNA (tRNA), which is needed for decoding the genetic message contained in mRNA; and (4) ribosomal RNA (rRNA), which forms part of the structure of ribosomes. The DNA that codes for rRNA synthesis is located in the part of the nucleus called the nucleolus. The DNA that codes for pre-mRNA and tRNA synthesis is located elsewhere in the nucleus. PROTEIN SYNTHESIS AND SECRETION For a gene to be expressed, it first must be used as a guide, or template, in the production of a complementary strand of messenger RNA. This mRNA is then used as a guide to produce a particular type of protein whose sequence of amino acids is determined by the sequence of base triplets (codons) in the mRNA. When mRNA enters the cytoplasm, it attaches to ribosomes. A ribosome comprises four molecules of ribosomal RNA and 82 proteins arranged to form two subunits of unequal size. The mRNA passes through a number of ribosomes to create a “string-of-pearls” structure called a polyribosome (or polysome, for short). The association of mRNA with ribosomes is needed for the process of genetic translation—the production of specific proteins according to the code contained in the mRNA base sequence. Each mRNA molecule contains several hundred or more nucleotides, arranged in the sequence determined by complementary base pairing with DNA during transcription (RNA synthesis). Every three bases, or base triplet, is a code word— called a codon—for a specific amino acid. Sample codons and their amino acid “translations” are listed in Table 1 and illustrated in figure below. As mRNA moves through the ribosome, the sequence of codons is translated into a sequence of specific amino acids within a growing polypeptide chain. Transcription and translation. The genetic code is first transcribed into base triplets (codons) in mRNA and then translated into a specific sequence of amino acids in a polypeptide. Selected DNA Base Triplets and mRNA Codons Functions of the Endoplasmic Reticulum and Golgi Complex Proteins that are used inside the cell are usually made by groups of ribosomes called polyribosomes, which float freely in the cytoplasm without attaching to other parts of the cell. But when a protein needs to be sent outside of the cell, it is made by ribosomes attached to the rough endoplasmic reticulum (ER). The rough ER has fluid-filled spaces called cisternae, where the new proteins go after they are made. Inside the cisternae, the proteins are modified in specific ways. When proteins meant for secretion (sending outside the cell) are made, the first 30 amino acids are hydrophobic (they don’t mix with water). This starting sequence helps the protein get into the membrane of the ER. As the protein chain gets longer, it is pushed into the cisterna. The starting sequence acts like an “address” that guides the protein into the ER. Once inside, this sequence is removed so the protein stays in the ER and doesn’t go back into the cytoplasm. A protein destined for secretion begins with a leader sequence that enables it to be inserted into the cisterna (cavity) of the endoplasmic reticulum. Once it has been inserted, the leader sequence is removed and carbohydrate is added to the protein. The processing of the hormone insulin can serve as an example of the changes that occur within the endoplasmic reticulum. The original molecule enters the cisterna as a single polypeptide composed of 109 amino acids. This molecule is called preproinsulin. The first 23 amino acids serve as a leader sequence that allows the molecule to be injected into the cisterna within the endoplasmic reticulum. The leader sequence is then quickly removed, producing a molecule called proinsulin. The remaining chain folds within the cisterna so that the first and last amino acids in the polypeptide are brought close together. Enzymatic removal of the central region produces two chains—one of them 21 amino acids long, the other 30 amino acids long—that are subsequently joined together by disulfide bonds (fig). This is the form of insulin that is usually secreted from the cell. The conversion of proinsulin into insulin. The long polypeptide chain called proinsulin is converted into the active hormone insulin by enzymatic removal of a length of amino acids (shown in green). The insulin molecule produced in this way consists of two polypeptide chains (red circles) joined by disulfide bonds. DNA SYNTHESIS AND CELL DIVISION When a cell is going to divide, each strand of the DNA within its nucleus acts as a template for the formation of a new complementary strand. Organs grow and repair themselves through a type of cell division known as mitosis. The two daughter cells produced by mitosis both contain the same genetic information as the parent cell. Gametes contain only half the number of chromosomes as their parent cell and are formed by a type of cell division called meiosis. DNA Replication When a cell is going to divide, each DNA molecule replicates itself, and each of the identical DNA copies is thus produced and distributed to the two daughter cells. Replication of DNA requires the action of a complex composed of many enzymes and proteins. As this complex moves along the DNA molecule, certain enzyme (DNA helicases) break the weak hydrogen bonds between complementary bases to produce two free strands at a fork in the double-stranded molecule. As a result, the bases of each of the two freed DNA strands can bond with new complementary bases (which are part of nucleotides) that are available in the surrounding environment. According to the rules of complementary base pairing, the bases of each original strand will bond with the appropriate free nucleotides—adenine bases pair with thymine-containing nucleotides, guanine bases pair with cytosine-containing nucleotides. Enzymes called DNA polymerases join the nucleotides together to form a second polynucleotide chain in each DNA that is complementary to the first DNA strand. In this way, two new molecules of DNA, each containing two complementary strands, are formed. Thus, two new double-helix DNA molecules are produced that contain the same base sequence as the parent molecule. The replication of DNA. Each new double helix is composed of one old and one new strand. The base sequence of each of the new molecules is identical to that of the parent DNA because of complementary base pairing. The Cell Cycle Unlike the life of an organism, which can be viewed as a linear progression from birth to death, the life of a cell follows a cyclical pattern. Each cell is produced as a part of its “parent” cell; when the daughter cell divides, it in turn becomes two new cells. In a sense, then, each cell is potentially immortal as long as its progeny can continue to divide. Some cells in the body divide frequently; the epidermis of the skin, for example, is renewed approximately every two weeks, and the stomach lining is renewed every two or three days. Other cells, such as striated muscle cells in the adult, do not divide at all. All cells in the body, of course, live only as long as the person lives (some cells live longer than others, but eventually all cells die when vital functions cease). The nondividing cell is in a part of its life cycle known as interphase (fig), which is subdivided into G1, S, and G2 phases. The chromosomes are in their extended form, and their genes actively direct the synthesis of RNA. Through their direction of RNA synthesis, genes control the metabolism of the cell. The cell may be growing during this time, and this part of interphase is known as the G1 phase (G stands for gap). Although sometimes described as “resting,” cells in the G1 phase perform the physiological functions characteristic of the tissue in which they are found. The DNA of resting cells in the G1 phase thus produces mRNA and proteins If a cell is going to divide, it replicates its DNA in a part of the interphase known as the S phase (S stands for synthesis). Once DNA has replicated in the S phase, the chromatin condenses in the G2 phase to form short, thick structures by the end of G2. The structure of a chromosome after DNA replication. At this stage, a chromosome consists of two identical strands or chromatids. Though condensed, the chromosomes are not yet in their more familiar, visible form in the ordinary (light) microscope; these will first make their appearance at prophase of mitosis  Cyclins and p53 A group of proteins known as the cyclins—because they accumulate before mitosis and then are rapidly destroyed during cell division—promote different cell cycle phases. During the G1 phase of the cycle, for example, an increase in the concentration of cyclin D proteins within the cell acts to move the cell quickly through this phase. Cyclin D proteins activate a group of otherwise inactive cyclin-dependent kinases. Overactivity of a gene that codes for cyclin D might be predicted to cause uncontrolled cell division, as occurs in cancer. Indeed, overexpression of the gene for cyclin D1 has been shown to occur in some cancers, including those of the breast and oesophagus. Genes that contribute to cancer are called oncogenes. Oncogenes are altered forms of normal proto-oncogenes, which code for proteins that control cell division and apoptosis (cell suicide). Conversion of proto-oncogenes to active oncogenes occurs because of genetic mutations and chromosome rearrangements (including translocations and inversions of particular chromosomal segments in different cancers). Whereas oncogenes promote cancer, other genes—called tumour suppressor genes—inhibit its development. One very important tumour suppressor gene is known as p53. This name refers to the protein coded by the gene, which has a molecular weight of 53,000. The p53 is a transcription factor: a protein that can bind to DNA and activate or repress a large number of genes. When there is damage to DNA, p53 acts to stall cell division, mainly at the G1 to S checkpoint of the cell cycle. Depending on the situation, p53 could help repair DNA while the cell cycle is arrested, or it could help promote apoptosis (cell death, described shortly) so that the damaged DNA isn’t replicated and passed on to daughter cells. Cell Death Cell death occurs both pathologically and naturally. Pathologically, cells deprived of a blood supply may swell, rupture their membranes, and burst. Such cellular death, leading to tissue death, is known as necrosis. In certain cases, however, a different pattern is observed. Instead of swelling, the cells shrink. The membranes remain intact but become bubbled, and the nuclei condense. This process was named apoptosis (from a Greek term describing the shedding of leaves from a tree). Two pathways lead to apoptosis: extrinsic and intrinsic. In the extrinsic pathway, extracellular molecules called death ligands bind to receptor proteins on the plasma membrane called death receptors. In the intrinsic pathway, apoptosis occurs in response to intracellular signals. This may be triggered by DNA damage, for example, or by reactive oxygen species that cause oxidative stress. Cellular stress signals produce a sequence of events that make the outer mitochondrial membrane permeable to cytochrome c and other mitochondrial molecules, which leak into the cytoplasm and participate in the next phase of apoptosis. The intrinsic and extrinsic pathways of apoptosis activate a group of previously inactive cytoplasmic enzymes known as caspases. Caspases have been called the “executioners” of the cell, activating processes that lead to DNA fragmentation and cell death. Apoptosis is a normal, physiological process that helps the body eliminate cancerous cells with damaged DNA. Mitosis At the end of the G2 phase of the cell cycle, which is generally shorter than G1, each chromosome consists of two strands called chromatids joined together by a centromere (prev.fig.). The two chromatids within a chromosome contain identical DNA base sequences because the semiconservative replication of DNA produces each. Each chromatid, therefore, includes a complete double-helix DNA molecule that is a copy of the single DNA molecule existing before replication. Each chromatid will become a separate chromosome once mitotic cell division has been completed. The G2 phase completes the interphase. The cell proceeds through the various stages of cell division, or mitosis. This is the M phase of the cell cycle. Mitosis is subdivided into four stages: prophase, metaphase, anaphase, and telophase (fig.). In prophase, chromosomes become visible as distinctive structures. In the metaphase of mitosis, the chromosomes line up a single file along the cell’s equator. This aligning of chromosomes at the equator is believed to result from the action of spindle fibres, which are attached to a protein structure called the kinetochore at the centromere of each chromosome (fig.). Anaphase begins when the centromeres split apart and the spindle fibres shorten, pulling the two chromatids in each chromosome to opposite poles. Each pole therefore gets one copy of each of the 46 chromosomes. During early telophase, division of the cytoplasm (cytokinesis) results in the production of two daughter cells that are genetically identical to each other and to the original parent cell. Hypertrophy and Hyperplasia The growth of an individual from a fertilised egg into an adult involves an increase in the number of cells and an increase in the size of cells. Change due to an increase in cell number results from an increased rate of mitotic cell division and is termed hyperplasia. The growth of a tissue or organ due to increased cell size is termed hypertrophy. Most growth is due to hyperplasia. For example, a callus on the palm involves thickening of the skin by hyperplasia due to frequent abrasion. By contrast, an increase in skeletal muscle size due to exercise is produced by hypertrophy. Meiosis When a cell is going to divide, either by mitosis or meiosis, the DNA is replicated (forming chromatids), and the chromosomes become shorter and thicker. At this point, the cell has 46 chromosomes, each consisting of two duplicate chromatids. The short, thick chromosomes seen at the end of the G2 phase can be matched as pairs, the members of each pair appearing to be structurally identical. These matched chromosomes are called homologous chromosomes. One member of each homologous pair is derived from a chromosome inherited from the father, and the other member is a copy of one of the chromosomes inherited from the mother. Homologous chromosomes do not have identical DNA base sequences; one member of the pair may code for blue eyes, for example, and the other for brown eyes. There are 22 homologous pairs of autosomal chromosomes and one pair of sex chromosomes, described as X and Y. Females have two X chromosomes, whereas males have one X and one Y chromosome. Meiosis, which has two divisional sequences, is a special type of cell division that occurs only in the gonads (testes and ovaries), where it is used only in the production of gametes—sperm cells and ova. In the first division of meiosis, the homologous chromosomes line up side by side, rather than a single file, along the cell's equator. The spindle fibres then pull one member of a homologous pair to one pole of the cell and the other member of the pair to the other pole. Each of the two daughter cells thus acquires only one chromosome from each of the 23 homologous pairs contained in the parent. In other words, the daughter cells have 23 rather than 46 chromosomes. For this reason, meiosis (from the Greek meion = less) is also known as reduction division. Meiosis, or reduction division. In the first meiotic division, the homologous chromosomes of a diploid parent cell are separated into two haploid daughter cells. Each of these chromosomes contains duplicate strands, or chromatids. In the second meiotic division, these chromosomes are distributed to two new haploid daughter cells. At the end of this cell division, each daughter cell contains 23 chromosomes, but each consists of two chromatids. (Since the two chromatids per chromosome are identical, this does not make 46 chromosomes; there are still only 23 different chromosomes per cell.) A second meiotic division separates the chromatids. Each daughter cell from the first cell division divides, with the duplicate chromatids going to each of the two new daughter cells. A grand total of four daughter cells can thus be produced from the meiotic cell division of one parent cell. This occurs in the testes, where one parent cell has four sperm cells. In the ovaries, one parent cell produces four daughter cells, but three die, and only one becomes a mature egg cell. The stages of meiosis are subdivided according to whether they occur in the first or the second meiotic cell division. These stages are designated as prophase I, metaphase I, anaphase I, telophase I; and then prophase II, metaphase II, anaphase II, and telophase II. The reduction of the chromosome number from 46 to 23 is obviously necessary for sexual reproduction, where the sex cells join and add their content of chromosomes together to produce a new individual. The significance of meiosis, however, goes beyond the reduction of chromosome number. At metaphase I, the pairs of homologous chromosomes can line up with either member facing a given pole of the cell. (Recall that each member of a homologous pair came from a different parent.) Maternal and paternal members of homologous pairs are thus randomly shuffled. Hence, when the first meiotic division occurs, each daughter cell will obtain a complement of 23 chromosomes that are randomly derived from the maternal or paternal contribution to the homologous pairs of chromosomes of the parent cell. In addition to this “shuffling of the deck” of chromosomes, exchanges of parts of homologous chromosomes can occur at prophase I. That is, pieces of one chromosome of a homologous pair can be exchanged with the other homologous chromosome in a process called crossing-over (fig. 3.31). These events together result in genetic recombination and ensure that the gametes produced by meiosis are genetically unique. This provides additional genetic diversity for organisms that reproduce sexually, and genetic diversity is needed to promote the survival of species over evolutionary time Epigenetic Inheritance Genetic inheritance is determined by the sequence of DNA base pairs in the chromosomes. However, as previously discussed, not all of these genes are active in each cell of the body. Some genes are switched from active to inactive, and back again, as required by a particular cell; activity of these genes is subject to physiological regulation. Other genes may be permanently silenced in all the cells in a tissue, or even in all of the cells in the body. Such permanent gene silencing occurs either in the gametes (and so is inherited) or in early embryonic development. Because the silencing of these genes is carried forward to the daughter cells through mitotic or meiotic cell division, without a change in the DNA base sequence, this is called epigenetic inheritance. Gene silencing is accomplished by (1) methylation of cytosine bases (specifically those that precede guanine in the DNA); and (2) (2) posttranslational modifications of histone proteins. This is accomplished by such changes as acetylation and methylation of the histones, which modify gene expression by influencing how tightly or loosely the chromatin is compacted. Through these means, only one allele (gene) of a pair (from the maternal or paternal chromosomes) may be expressed, and only one X chromosome of the two Xs in female cells is active. Because of epigenetic changes in the DNA and histone proteins, even identical twins can have differences in gene expression. Problems with epigenetic inheritance are known to contribute to several diseases, including cancer, fragile X syndrome, and systemic lupus erythematosus. For example, methylation of cytosine bases is an epigenetic mechanism for long-term gene silencing; thus, it may not be surprising that cancers show a global (widespread) reduction in DNA methylation. This is associated with the activation of genes and instability of chromosome structure in cells that have become transformed in a tumour. However, not all genes are Activated; many cancers have inactivated tumour suppressor genes, as well as a generally reduced expression of microRNA (miRNA) genes. Crossing-over. (a) Genetic variation results from the crossing-over of tetrads, which occurs during the first meiotic prophase. (b) A diagram depicting the recombination of chromosomes that occurs as a result of crossing-over.