Telomeres In Dna Replication Biology Essay

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The terminal regions of linear chromosomes are capped with telomeres; a distinct DNA-protein sequence. This capping provides protection for the 3G rich end of the choromosome from degradation. Telomeres are nucleoprotein structures consisting of several repeats of a hexameric DNA sequence, which exists as 'TTAGGG' in mammalian cells, which also contain telomere - associated proteins. (Shay and Wright, 2005). Telomeres help in maintaining genetic material within linear chromosomes, preventing genomic instability in eukaryotes and the loss of useful chromosomes. This essay will depict the roles of telomeres in DNA replication, stability and cellular senescence.

Double strand breaks (DSB) that occur in genomic DNA within a chromosome are identified via telomeres. DSB's are extremely harmful and can cause chromosomal deletions. If recombination occurs at telomeres the length of the telomere may increase or decrease either engaging or inhibiting senescence. Telomeres help in identifying chromosome ends in damaged DNA and without telomeres the ends of chromosomes may randomly fuse with each other causing dicentric chromosomal structures that interfere with the progression of the cell cycle; provoking genomic instability. (Campisi et al, 2001)

TELOMERASE

Telomerase carries out De Novo synthesis of telomeric DNA in eukaryotes via ribonucleoprotein reverse transcriptas telomerase that consists of two subunit; the enzymatic human telomerase reverse transcriptase subnit hTERT and the RNA subunit. (Wyatt et al, 2010). The RNA subunit manufactures telomeric DNA that is added to the chromosome ends. Every sixth nucleotide telomerase translocates the template RNA in order to manufacture the following six base pairs. This extension of the chromosome allows the replication of the C rich strand, which prevents end replication problems. (Shay and Wright, 2005).

TELOMERE LENGTH & STRUCTURE

The typical structure of telomeres consist of telomere binding proteins in a large loop that is slightly lasso-shaped known as the 't-loop.' It ensures that the telomere itself is hidden from being mistaken as broken DNA in conjunction to telomere- associated proteins that act a protective 'cap' maintaining the length of the telomere; protecting it from degradation. (Wyatt et al, 2010). Studies by Wyatt et al, 2010, have recognised this t loop structure in a range of species including, plants, nematodes and some forms of yeast.

The 3' overhang is embedded in the telomeric DNA, which is in the junction between the lasso circle and tail. It can be argued that the existence of the t loop regulates the access of telomerase to its substrate and also prevents the 3'overhang from degradation. (Shay and Wright, 2005). Mammalian chromosomes have a 3' 'overhang' at both ends, suggesting that a 3' tail is necessary for enabling a stable structure for telomeres. Telomere structures are managed via telomere - associated proteins that are aggravated through regular cellular processes i.e. proliferation and differentiation etc. (Campisi et al, 2001)

DNA REPLICATION

Somatic cells cannot express telomerase in contrast to germ line cells, which proves to be a problem for cell division and in DNA replication. During the cell cycle telomeres shorten in the 'S phase' posing three problems within DNA replication: DNA replication is bidirectional, DNA polymerases are unidirectional and DNA polymerases need to start replication at a primer. Around 50-200 base pairs of DNA remain at the end of each stage of DNA replication. The average length of a telomere is 4-6kb; which is where cellular senescense occurs.

Studies have shown that the expression of telomerase can occur in certain adult somatic cells and it can argued that telomerase cannot inhibit telomere erosion that occurs during DNA replication. However studies by Bodner et al, 1998 have shown that telomere erosion can be stopped via the ectopic expression of telomerase. It cannot be determined as to whether telomerase will or wont prevent the shortening of telomeres during DNA replication however there a few factors that help in understanding how it occurs. Firsty, the level of telomerase expressed may constrain the elongation of telomere, secondly, the availability of the telomerase to the 3' overhang can be maintained via telomere-associated proteins and thirdly, the action of telomerase on a particular telomere is regulated via checkpoint proteins. Reference!

CELLULAR SENESCENCE

Telomeres that undergo cellular senescence are mainly dysfunctional. Cellular senescence stops cell proliferation and disturbs the functioning of cells, irreverisibly. It usually occurs when healthy cells come into contact with oncogenic material and dysfunctional telomeres and through mutant oncogenes i.e. RAS. Cells affected produce a high volume of 'growth inhibitory genes' and also cannot grow further and proceed onto the further steps of the cell cycle. Senescense in mammalian cells start at a length between 4-7kb. Telomerase can prohibit telomere dependant senescense but cannot prohibit telomere independent senescence. (Campisi et al, 2001)

P53 regulates the interactions in cell cycle apoptosis and it has been found that the inactivation of p53 tumor suppressor proteins can prevent cellular cenescense. If a mutation occurs in the p53 protein, senescense will be revoked i.e human fibroplasic cells that do not contain the p53 protein will not proliferate further. Telomeres shorten rapidly when p53 is absent becoming highly unstable. Such telomeres try to proliferate but die as a consequence of chromosomal instability. Short telomeres are lengthened in the presence of telomeres which inhibits the form of fusions. (Blasco, 2003).

The lack of telomeres has a negative effect on the cell cycles and cause replicative senescence (RS). Research carried out by Shay and Wright, 2005, have shown that around 60-85% of the 3' G rich overhang corrodes; whereby the cells shorten after the bypassing of M1. Usually the duration of telomere sensescnse is determined by the shortest telomere. (Shay and Wright, 2005)

GENOMIC INSTABILITY

A telomere absent chromosome is naturally very unstable, being highly susceptible to degradation or the fusing of one chromosome end to a DSB. The fusion of chromosomes leads to the production of dicentric chromosomes that lyse during the cell cycle and ring and other unstable forms of a chromosome however the configuration of telomeres inhibit the fusing of chromosome ends; ensuring that the stability of eukaryotic genomes are maintained. The dysfunction of chromosomes further occurs in genomic instability in addition to the absence of p53. If a telomere is unstable, genetic material is lost making the cell unviable; enhancing the chances for mutations to occur in order to acquire a stable structure. A telomere's most common method of attaining a more stable structure is via telomerase. (Campisi et al, 2001)

CANCER

Telomeres play major roles in diseases such as pulmonary fibrosis and bone morrow failure however are most observed in cancer cells. Tumours in cancel cells can generally avoid cell senesecnse and continue to proliferate. However, if any of the checkpoint pathways are interfered with, cell life increases in conjunction with the loss of telomeres. Each round of cell division causes the shortening of telomeres without the addition of telomerase which triggers the 'p53 and pRB dependant DNA damage response' (Wyatt et al, 2010) which further provokes replicative senescence (M1). Cells with the p53 and pRB damaged pathways will carry out between 20-30 rounds of cell division where telomeres continues to shorten and chromosomes will underogo end to end fusion promoting genomic instability. As this continues 'crisis' occurs (M2) where certain mutations arise due to the upregulation of telomerase; which shortens telomeres allowing further rounds of cell division unnecessarily. M2 causes the uncapping of chromosomes, fusing of ends and chromosomes breakages and sometimes the apopsis of cells. REFERENCE.

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