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The cell cycle: What do you need to know about it ?

Paul R. Earl
Facultad de Ciencias Biológicas Universidad Autónoma de Nuevo León San Nicolás, NL, Mexico

Cytology is simply any study of the cell, although by a long tradition, study by the light microscope is implied. Cytology is often connected with genetics to become cytogenetics as developed over a century ago in Europe, and then mainly by the Thomas Hunt Morgan (1866-1945) school of Columbia University in New York with Calvin Bridges (1889-1938) and Alfred Sturtevant (1891-1970), and also Hermann Muller (1890-1967). In 1902 & 1903, Walter Sutton (1877-1916) and Theodor Boveri (1862-1915) had refined gametic meiosis that explains Mendelism.

Boveri had named the centromere in 1901. In 1914, Boveri proposed his supertheory that aneuplody causes cancer. In 1910-1913, Morgan and Bridges established that the genes were in the chromosomes, and Sturtevant who wrote The History of Genetics (1965) found that the genes were arranged in a line. Imagine the problem if they were not ! By 1927, Hermann Muller (1890-1967) of the Columbia group found that X-rays caused chromosome breaks and increased the mutation rate. Another powerful contributor to cytology was Cyril Darlington (1903-1981) on gametic

Cytogenetics is chiefly the visible knowlege obtained with various kinds of microscopes. Genetics is the body of inferred knowledge obtained by all means of study, including, for instance, PCR. See Blystone R. 2003. WWW.Cell Biology Education. Cell Biol Ed 2: 214–219, also vysa.com and cytocell.co.uk, and www.molbiolcell .org/cgi/doi/10.1091/ mbc .E03–11–0794.

Meiosis contains a reduction division. When the chromosomes are halved before mating which likely involves crossingover, haploid (single set) gametes are formed. This is 1 + 1 = 2 as 23 haploid plus 23 haploid = the 46 diploid set of chromosomes in humans. Twenty-two pairs are autosomes, whereas X & Y are female (XX) and male (YX) sex chromosomes, verified long ago by Stevens. When the number of chromosomes is doubled to form a karyosome (synkaryon) or fertilization nucleus, then reduced immediately or in the 2nd division, this is zygotic or haploid meiosis as 1 + 1 = 2, then 2 =-1 + 1. Zygotic meiosis occurs in some protozoans, fungi and yeasts. Then the soma of algae like Spirogyra is haploid. Meiosis =

In the 1st meiotic division--reduction--2 successive rounds of chromosome segregation follow a single round of DNA duplication, producing 4 haploid products. The segregation of homologous pairs of chromosomes at the 1st division is dependent on their previous pairing, synapsis and recombination from crossingover at earlier stages. The 2nd meiotic division serves to separate the 2 sister chromatids of each chromosome. Subsequent fertilization of male and female gametes restores the diploid state.

Mitosis in salamander skin as illustrated here was drawn by Flemming in 1882. In a-c prophase chromosomes are condensing and later aligning to move towards the metaphase plate (i). Metaphase, d-f, contains 2 sets of chromosomes that separate during anaphase, g-h. In telophase is i-j or even g-j, if you like. Karl von Nägeli (1817-1891) noted chromosomes in 1842 so named in 1888 by Heinrich WG Waldeyer-Hartz (1836-1921).

The entire cytological advance depended on selective dyes that were developed by the German chemical industry in the 19th century. During meiosis, homologous maternal and paternal chromosomes become linked by cytologically observable connections that are chiasmata (breaks and bridges). Each chiasma is the site of a DNA crossover between one sister of

The Hayflick limit
Long ago and far away, the Algerian librarian Emile Maupas (1844-1916) in 1889 found that clones of the ciliate Paramecium eventually died out, yet he also discovered that these ciliates were rejuvenated if fertilized. By 1959 at the Wistar Institute in Philadelphia, published in 1965, Lennie Hayflick found that normal human diploid primary cell lines would only grow in tissue culture for some 50 plus generations. He was looking for a cheaper way to grow polio virus than in primary rhesus kidney cells. They, like all normal cells, died out after a very few months.

The cell cycle has 2 phases: interphase and mitosis. Interphase consists of G1, S and G2 phases. Growth 1 & 2, and DNA Synthesis. Mitosis can be subdivided into: 1/ prophase, 2/ metaphase, 3/ anaphase and 4/ telophase. Chromosomes condense during prophase, align during metaphase, separate during anaphase and decondense during telophase. There are several control checkpoints during the cell cycle. One in late G1 is Start in yeast called the Restriction point in mammals. It is active in late G2 and just

PROPHASE •The 2 centrosomes of the cell, each with its pair of centrioles, move to opposite poles of the cell. •The spindle polar body forms an array of about 20 spindle fibers each, growing out from each centrosome. • Chromosomes condense to become shorter and more compact.

CYTOKINESIS is cytoplasmic division as karyokinesis is nuclear movement that is equal to nuclear division. A typical centrosome is about 1 µm3 in volume and composed of a pair of centrioles surrounded by a matrix of pericentriolar material. The centrioles consist of a cylinder formed by microtubules arranged with perfect nine-fold symmetry. The pericentriolar matrix contains several large coiled-coil proteins and the tubulin ring complex. The centrosome does not have a membrane.

Animal cells have one centrosome in G1 phase of the cell cycle that duplicates once in the S phase to form a bipolar spindle during mitosis. The duplication of centrioles is semiconservative--one old, one new. The 2 original centrioles separate and a new centriole grows adjacent to each to form 2 complete centrosomes. Tubulin subunits as in the centrioles are in abundance. In animal cells, a belt of actin filaments forms around the perimeter of the cell midway between the poles. The interaction of actin and a myosin (not the one found in skeletal muscle!) tightens the belt, pinching it into 2 daughter cells.

Checkpoints
We mentioned Start. To pass each point, cells have to fulfil several prerequisites. Before passing Start, cells can undergo 2 developmental programs, vegetative reproduction--mitosis or sexual development--meiosis. A cell must replicate all of its components and divide them into 2 nearly identical daughter cells. As DNA stores the genetic information, it must be accurately replicated in the S phase of the cycle. DNA duplication results in 2 identical sister chromatids, which must be precisely segregated. Segregation of sister-chromatids happens during mitosis

G0 is interphase lasting for days at least. Also, adequate nutritional conditions and a critical cell size are required to engage Start. During G2, cells have to check whether DNA replication is completed and ensure that DNA is undamaged. Before chromosome separation, cells check whether the chromosomes are aligned and spindle polar body are formed properly.

Meiosis
In gametic meiosis I division (MI), the homologous chromosomes separate, but the sister chromatids remain attached, thus going to the same pole. This is the reductional division, because it essentially reduces the ratio of chromosomes in the daughter nuclei from 2 to 1. In zygotic meiosis, the karyosome in 1 or 2 steps will segregate the zygote into 2 haploid sets. You must be very clear about the natural consequences of the reduction, and, in yeast, possibly look for controls for

A

B

Three irreversible transitions are present in the mitotic cycle: 1/ Start, when the cell commits itself to cell division, 2/ G2/M Transition, when the cell commits itself to enter into mitosis, and 3/ Finish, when the cell exits from mitosis (ana- phase, telophase, cell division). Cells are driven through the cell cycle by an underlying molecular engine of protein molecules.

In higher eukaryotes, many Cdk–cyclin complexes trigger different cell-cycle events. In lower eukaryotes, like fission yeast, a single Cdk–cyclin complex can drive the whole cell cycle. This complex is called Cdc2–Cdc13 in fission yeast: Cdc2 is the Cdk subunit and Cdc13 is the major B-type cyclin in fission yeast cells. Cdc2 is present at a constant level throughout the cell cycle, and it is in excess over Cdc13. Cdc13 is continuously synthesized and it combines with Cdc2 to form an active Cdk–cyclin complex. Study the diagram

By now, we have covered What You Need to Know about the Cell Cycle. Two special topics are now noted: Pap smears (George Papanicolaou, 1883-1962) and Fluorescence in situ hybridization (FISH). In addition, a Glossary is added and a list of over 200

References.