1. Describe the physical structure of chromosomes what makes up the centromere and telomere of chromosomes. Chromosomes consist of a single molecule of DNA associated with many copies of 5 kinds of histones. Histones are proteins rich in lysine and arginine residues and thus positively-charged. For this reason they bind tightly to the negatively-charged phosphates in DNA and a small number of copies of many different kinds of non-histone proteins. Most of these are transcription factors that regulate which parts of the DNA will be transcribed into RNA.
For most of the life of the cell, chromosomes are too elongated and tenuous to be seen under a microscope. Before a cell gets ready to divide by mitosis, each chromosome is duplicated (during S phase of the cell cycle). As mitosis begins, the duplicated chromosomes condense into short (~ 5 µm) structures which can be stained and easily observed under the light microscope. These duplicated chromosomes are called dyads. When first seen, the duplicates are held together at their centromeres. In humans, the centromere contains 1–10 million base pairs of DNA.
Most of this is repetitive DNA: short sequences repeated over and over in tandem arrays. While they are still attached, it is common to call the duplicated chromosomes sister chromatids, but this should not obscure the fact that each is a bona fide chromosome with a full complement of genes. The kinetochore is a complex of >100 different proteins that forms at each centromere and serves as the attachment point for the spindle fibers that will separate the sister chromatids as mitosis proceeds into anaphase. The shorter of the two arms extending from the centromere is called the p arm; the longer is the q arm.
Staining with the trypsin-giemsa method reveals a series of alternating light and dark bands called G bands. G bands are numbered and provide “addresses” for the assignment of gene loci. Telomeres. Each eukaryotic chromosome consists of a single molecule of DNA associated with a variety of proteins. The DNA molecules in eukaryotic chromosomes are linear; i. e. , have two ends. The DNA molecule of a typical chromosome contains a linear array of genes (encoding proteins and RNAs) interspersed with much noncoding DNA.
Included in the noncoding DNA arelong stretches that make up the centromere and long stretches at the ends of the chromosome, the telomeres. Telomeres are crucial to the life of the cell. They keep the ends of the various chromosomes in the cell from accidentally becoming attached to each other. The telomeres of humans consist of as many as 2000 repeats of the sequence 5′ TTAGGG 3′. 2. Review briefly the process of replication of linear chromosomes. What accountsfor the natural shortening of the lagging strand.
DNA polymerase can only synthesize a new strand of DNA as it moves along the template strand in the 3′ –> 5′ direction. This works fine for the 3′ –> 5′ strand of a chromosome as the DNA polymerase can move uninterruptedly from an origin of replication until it meets another bubble of replication or the end of the chromosome. However, synthesis using the 5′ –> 3′ strand as the template has to be discontinuous. When the replication fork opens sufficiently, DNA polymerase can begin to synthesize a section of complementary strand — called an Okazaki fragment — working in the opposite direction.
Later, a DNA ligase (“DNA ligase I”) stitches the Okazaki fragments together. The horizontal black arrows show the direction that the replication forks are moving. Wherever the replication fork of a strand is moving towards the 3′ end, the newly-synthesized DNA (red) begins as Okazaki fragments (red dashes). This continues until close to the end of the chromosome. Then, as the replication fork nears the end of the DNA, there is no longer enough templates to continue forming Okazaki fragments. So the 5′ end of each newly-synthesized strand cannot be completed.
Thus each of the daughter chromosomes will have a shortened telomere. It is estimated that human telomeres lose about 100 base pairs from their telomeric DNA at each mitosis. This represents about 16 TTAGGG repeats. At this rate, after 125 mitotic divisions, the telomeres would be completely gone. Is this why normal somatic cells are limited in the number of mitotic divisions before they die out? 3. What is CELLULAR SENESCENCE? Expound on some mechanisms that accounts for cellular senescence. (telomeric shortening, accumulation of damage, cross linking / glycation and mitochondrial damage theories).
What are the properties of cell during its senescent phase? How cellular senescence is related to cancer. Senescence is a metabolically active form of irreversible growth arrest that halts the proliferation of ageing and/or damaged cells and as a consequence, prevents the transmission of damage to daughter cells. Cellular senescence is controlled by tumor suppressor genes (p53,p21,RB,Bax,Bub1p) and seems to involve a checkpoint that prevents the growth of cells at risk for neoplastic transformation.
In this regard, cellular senescence is similar to apoptosis However, whereas apoptosis kills and eliminates damaged or potential cancer cells, cellular senescence involves a stable arrest of growth. Classically, as shown on the left, DDR signals are sensed by the p53 and p16/pRB pathways, leading to senescence of the cell. On the other hand, as shown on the right, when signaling cascades in the tumor-suppressing p53 and/or p16/pRB are partially or completely blocked, cells fail to undergo senescence in response to stimulating “Hayflick factors”.
These cells are at a particularly high risk for developing cancers when additional oncogenic events occur. Of note, senescent cells have been suggested to prevent cancer in young organisms owing to their growth-static nature. However, in the aged population, senescence seems to contribute to aging in the whole organism. The senescent behavior of normal cells is associated with the loss of “telomerase activity”; the telomeres are no longer elongated, which contribute to the onset of senescence and cell death. Cancer cells have a high level of telomerase, which help to protect them from senescence, making them immortal.