Telomeres are specialised protein structures found on the terminal ends of chromosomes in eukaryotes. Unlike prokaryotic organisms that have circular DNA, eukaryotic organisms contain linear DNA which is more probable to undergo attack, leading to the degradation of the DNA. Telomeres therefore, play a crucial role in protecting the cells nuclear DNA, by forming a cap around the terminal ends of chromosomes. Furthermore, telomeres carry out several other essential roles, some of which include; maintaining the stability of chromosomes, enabling completion of DNA replication and also cellular senescence. All these roles are discussed in detail through this text.
Briefly discuss all the roles of telomeres
Also mention the telomeres are beneficial in preventing homologous recombination of chromosomes, as the broken ends of DNA are more prone to joining together.
What are telomeres and their structure
Telomeres are composed of a protein nucleic acid complex which consists of two main components; telomeric DNA and proteins. The telomeric DNA is commonly comprised of short tandem repeat units (6-8 nucleotides), and guanine (G) rich nucleotides that are grouped towards the end of the chromosome on the G-rich strand. This is the strand positioned 5' to 3' towards the terminal end of the chromosome (Blackburn, 2001). Typically in humans and most other eukaryotic organisms the sequence of repeat units is commonly AGGGTT. This sequence was proposed by Elizabeth H. Blackburn in 1991 through a series of experiments conducted in her early years of research (Blackburn, 1991). It was later published by Jeremy M. Berg and his fellow writers in a book, confirming the presence of this sequence in most eukaryotic organisms (Berg, 2012). It is estimated that this repeat sequence is present in every telomere within human cells, therefore, researchers have estimated that 0.02-0.06% of the genome is telomeric DNA by weight (Blackburn, 2001). Furthermore, the presence of this telomeric DNA sequence holds great importance towards DNA replication as it is responsible for the replication of the 5' end of the chromosome; this mechanism of action is later discussed.
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The second major component of telomeres, the proteins, also play a vital role towards the functioning of telomeres. Telomeres are unable to function effectively and efficiently without the presence of a DNA protein complex which should be bound to the nucleotide sequence on telomeres. The binding of this DNA protein complex is only possible when telomeric proteins recognise the nucleotide repeat units and bind to this successfully. This triggers the binding of other proteins present in the nucleoplasm, causing the formation of a DNA protein complex (Blackburn, 2001).
Furthermore another essential protein present in telomeres, is a specialized ribonucleoprotein enzyme known as telomerase. This enzyme is essential for the maintenance of the telomeres and also plays a key role towards DNA replication of the cell (Blackburn, 2001). Telomerase is composed of a catalytic core, comprising of a RNA subunit and a catalytic protein subunit. The RNA subunit acts as a template for the addition of nucleotides to the 3' end of chromosomes, during DNA replication. The protein subunit catalyses this reaction (Meyerson, 2000).
The role of telomeres in DNA replication
As discussed previously, the major component of telomeres which plays a vital role in DNA replication is telomerase. This is a specialised ribonucleoprotein which contains its own RNA template, for the replication of telomere DNA. During DNA replication a primer attaches itself to the 5' end of a chromosome strand. DNA polymerase then works to add nucleotides from the 5' to 3' direction on the sense strand. During this procedure, as the primer is attached to the 5' end of the chromosome, some genetic material from this section is not transcribed. Therefore the major role of telomeres during DNA replication is to ensure that no genetic material from the terminal ends of chromosomes is lost, and as a result telomeres function to replicate this un-transcribed region of DNA (Blackburn, 2001). Telomerase is a protein which assists this process through a reaction cycle. Initially telomerase binds to the telomeric primer on the single stranded DNA. This primer is formed naturally by the telomere as a result of the 3' overhang. Following this the first set of repeat nucleotides are synthesised. Deoxynucleotide triphosphates are added to the repeat units on the telomere causing it to lengthen and the genetic information to be replicated (Wyatt et al, 2010).
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Telomeres and stability
Telomeres are structures which are essential in order to maintain the stability of chromosomes. Without the presence of telomeres, chromosomes are likely to undergo degradation and recombination with other chromosomes. This is not beneficial to cells, for which reason the presence of telomeres is crucial to chromosomes. Research carried out by Wyatt in 2010 explains that earlier experimental procedures display the presence of structures known as telomere loops in chromosomes. Today it is believed that, the major reason why telomeres hold importance in protecting the nuclear DNA from degradation or fusion with other homologous chromosomes is due to the formation of these telomere-loops (t-loop). T-loops are formed due to the presence of several nucleotide repeats on a single strand of DNA, causing a 3' overhang, which results in the G-rich strand being longer than expected. As a result the DNA strand loops, forming the T-loop. Wyatt further explains in his research that previous experimental procedures on human and mice telomeric DNA display similar trends about T-loops when the telomeres of both organisms were viewed under an electron microscope (Wyatt, 2010). Overall, most importantly the formation of the T-loop protects the cell and gives the chromosome stability.
Furthermore, Wyatt and his fellow scientists also explain that the ribonucleoprotein, telomerase is also responsible for maintaining the stability of chromosomes. As mentioned previously the telomerase protein is composed of two subunits, one of which is the RNA subunit. This is further subdivided into two structural motifs known as a box H/ACA domain. This domain is the element of the RNA subunit which is responsible for the binding of proteins during the synthesis of telomeres and addition of nucleotides. Thus this motif is an essential structural component of telomeres, which is crucial to the stability of the telomere, as without the presence of these structural motifs, the telomeres would be unstable and probable to degradation (Wyatt, et al, 2010).
In comparison, research carried out by Deng and Chang in 2007 explains that telomerase is absent from somatic cells, for which reason after continuous DNA replication, the telomeres shorten as a result of no nucleotides being added to the telomeres via the ribonucleoprotein telomerase. Therefore as the age of an individual increases, the rate of cell death also increases. This shortening of telomeres eventually leads to their degradation converting them into double stranded breaks thus leading to the instability of the chromosomes.
Telomeres and cellular senescence
P53, towards the end, leads to senescence- as a result of telomere shortening, once the length of the telomeres reaches a critical threshold, which is a level where the length of the chromosome is too short to form a telomere loop and, hence paly a protective role towards the nuclear DNA of the cell, the cell initiates a p53 and pRB-dependant DNA damage response. This takes place in order to protect the cellular DNA of the cell and therefore the cell destroyed.
However, cells which have a defective p53 and pRB pathway, lead to the formation of cancer as, the cells continue to divide through a series of cell divisions. This in turn results in tumour cell formation and hence cancer.
Analysis of literature sources
The structure of telomeres is essential in enabling accurate and correct function of telomeres. The presence of the tandem repeat units coupled with the presence of telomeric DNA proteins are essential in order for the telomere complex to function appropriately.