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GENETICS OF AGING
In this essay I am going to investigate the importance of telomeres, their role in eukaryotic DNA replication, the importance of telomerase and shelterin complexes, the action of telomerase and most importantly how does telomere shortening cause the onset of Dyskeratosis congenita. ‘Dyskeratosis congenita is a rare syndrome of premature aging that was recognized as a clinical entity nearly a century ago’ (Masood A Shamas, 2011). It leads to a diverse range of phenotypes depending on the mode of inheritance and which of the main 6 genes associated with telomere maintenance and elongation have mutated.
Firstly, and probably the biggest, most exciting concept concerning genetic aging is the theory of telomere shortening and the action of telomerase. Telomeres are DNA protein complexes which are situated at both ends of both chromosomes. ‘They play a crucial role in protecting our genome from nucleolytic degradation, unnecessary recombination, repair, interchromosomal fusion and therefore preservation of the genetic information found with in our genome.’(Masood A Shamas 2011). Telomeres found in humans consist of a sequence of multiple repeats of TTAGGG and this can be repeated up to 3,000 times reaching a total of 15,000 bases long. The most important role this ribonucleoprotein plays is during DNA replication. This is due to eukaryotic chromosomes being linear, which unlike prokaryotic chromosomes, means that DNA located at the very end of the chromosome cannot be replicated.
During the process of DNA replication, one of the two new strands called the leading strand (grey strand as seen on the diagram) is being made continuously at the replication fork. Whilst the second strand called the lagging strand (blue strand as seen on the diagram) is being produced from many small pieces called Okazaki fragments, each of which begins with its own RNA primer (pink as shown on the diagram). During prokaryotic DNA replication, on the lagging strand the RNA primer will be removed by the 5’-3’ exonuclease activity of DNA polymerase and then DNA polymerase will replace the missing bases by complementary base pairing. And the nicks between the Okazaki fragments are joined by the enzyme ligase. However during eukaryotic division there is no way to start the Okazaki fragment at 5’ end of the chromosome, this is because the primer would fall beyond the chromosome end, and is therefore placed as much as 70-100 nucleotides away from the end. Also when the RNA primer required to make the last Okazaki fragment is removed DNA polymerase can no longer fit the gap and therefore cannot replace the missing bases by complementary base pairing. This therefore results in shortening of one 5’ end of each daughter DNA molecule, and with DNA replicating at a rate of up to 50 bases per second, repeated replication results in shorter and shorter DNA molecule and if this is not corrected eukaryotes would become extinct as their DNA would become destroyed, as a result eukaryotes have evolved a mechanism to preserve the ends of their chromosomes. This mechanism involves , the action of the enzyme telomerase and shelterin, a protein complex, that work together to add telomeric repeats to the chromosome ends to try and reverse this process of DNA shortening during replication. The action of telomerase and shelterin occurs particularly on quickly dividing cells such as germline, stem and hematopoietic cells, but is not present or found in small numbers on somatic cells.
The TERC and TERT genes contain the information in the form of base sequences for transcription and translation of the two principal proteins that make up telomerase, hTR and Htert. Htr is an RNA molecule. It contains the RNA sequence which acts as a template for the synthesis of complementary DNA (telomeric repeats), which is added by telomerase to the telomeres( chromosome ends). Whilst Htert’s job is to add new DNA segments to the chromosome ends.
Dyskerin, is another essential protein, coded for by the DKC1 gene, its function is to bind to Htr and secure the telomerase complex.
In addition to this, shelterin plays a protective role, sheltering the telomeres from the cells DNA repair process. If it wasn’t for the action of shelterin, the DNA repair process would think of the telomeres as unusual breaks in DNA sequence and would try to join the ends together or trigger apoptosis. The main protein in shelterin complex is coded for by the TIF2 gene.
Furthermore, telomerase is a very exclusive protein complex in the way that it has present DNA polymerase activity whilst also an RNA sequence which provides a template for the synthesis of telomeric repeat DNA, this type of molecule is known as an RNA- dependent DNA polymerase. Firstly, hybridization occurs between a section of the RNA sequence on the telomerase and the 3’ overhang of DNA forming a single stranded overhanging RNA sequence. Next the DNA polymerase activity of telomerase comes into action synthesising a complementary DNA strand to the RNA template of telomerase, it will then move to the end of the newly made strand, this sequence of events will keep repeating until telomerase has achieved its objective and detaches from the DNA strand. DNA primase will then make an RNA primer as close to 3’ end of overhanging DNA as possible, DNA polymerase is then implemented to add nucleotides by complementary base pairing in the region between the RNA primer and the 5’ end of the original DNA. However, as I mentioned above when the RNA primer is added to the 3’ end it is not added at the very end but as close to the end as possible, therefore leaving a very small section of the 3’ end still singley stranded. In conclusion although telomerase adds hundreds of bases to the end of the 3’ end during DNA replication the ends of the chromosomes will still shorten, although a lot more slowly thanks to the action of telomerase.
This continuous reduction in telomere size caused by the RNA primer not being placed right at the end of the chromosome causes ‘senescence, apoptosis, or oncogenic transformation of somatic cells’( Masood A Shamas, 2018), thus disturbing the health and lifespan of an individual, this is why shorter telomeres have been found to correlate with a high frequency of disease and an overall shorter lifespan. This highlights one of the reasons why your likelihood of developing a disease or illness increases with age and one example of this that I found particularly fascinating through doing my research is that of, dyskeratosis congenita. Dyskeratosis congenita, is a genetic disease which is caused by poor maintenance of telomeres, reduced telomere length and shows phenotypes of premature ageing. This disease affects cells rapidly dividing cells more harshly, therefore these cells suffer the consequences of telomere shortening causing notable symptoms: with nail dystrophy, bone marrow failure (where sufferers produce an inadequate number of red blood cells leading to bleeding and bleeding of the skin) pigmentation of the skin, oral leukoplakia, being the most common.
This leads me on to how does dyskeratosis congenita arise. Firstly as I explained above TERC plays an essential role in the reverse transcription process carried out by telomerase allowing telomeric repeats to be added to DNA during replication. Considering the parts of TERC complex more closely, we see the box H/ACA domain plays a key role, its role is to make sure the maturation and stability of the TERC complex is complete and thus the overall regulation of telomerase is carried out correctly. In mammals this domain is found to contain four protein subunits: Gar 1, dyskerin, Nop10 and Nhp2 and mutations within the Nop 10 (a substitution of base sequences from cytosine to thymine associated with autosomal inheritance) , Nhp2 (three single nucleotide polymorphisms, associated with autosomal inheritance ) and dyskerin 1(point mutations associated with X linked recessive inheritance) genes have been proven to cause dyskeratosis congenita . Furthermore, mutations in the TERT ( associated with autosomal dominant and recessive inheritance )and DKC1 genes have been found to cause dysfunction of telomerase whilst mutations in the TINF2 gene( associated with autosomal dominant inheritance ) have been found to cause mutations in the shelterin complex also leading to dyskeratosis congenita. With all these genes being involved in the maintenance and elongation of telomeres, when mutated it proves rapid shortening of telomeres is the underlying mechanism of this disease.
Furthermore with regards to inheritance patterns dyskeratosis congenita is found to also undergo an X linked recessive pattern, along with autosomal dominant and autosomal recessive. The X linked recessive pattern is induced by mutations on the DKC1 gene found on the distal portion ( more specifically band 28) of the long arm of the X chromosome ( Xq28). The DKC1 gene contains instructions for the synthesis of the dyskerin protein. As mentioned above dyskerin binds to Htr RNA molecule and stabilizes the telomerase complex whilst also playing a key role in ribosome synthesis. Point mutations are widley seen on the DKC1 gene which include either insertion or deletion of only one amino acid, leading to a frameshift mutation and the wrong amino acid encoded for, this is known as a missense mutation.
As these mutations are situated on the X chromosomes, this has big implications when it comes down to inheritance, as it explains to us why the X linked recessive disorder is more common in males as opposed to females. Firstly, as this is an X linked recessive disorder if only one X chromosome contained the mutation the female will only be a carrier of the disease, which is very common but if both the X chromosomes in females carry the mutated DKC1 gene symptoms of the disease will then arise, which is quite rare. However on the other side of the coin, as males have only a single X chromosome, if this chromosome contains the mutated DKC1 gene, and the offspring inherit this modified gene, they will be carries of the disease. Therefore only one mutated copy of the gene per cell in males is enough to generate the disease, whereas females must contain two mutated copies of the gene per cell to suffer from the disease.
Furthermore, another piece of evidence supporting this X linked recessive mutation is the fact that all the daughters of a male with the condition will all be carriers, whereas it is impossible for his sons to be carriers. This is because males with the mutation on X chromosome only pass their Y chromosome on to their male offspring not their X chromosome, proving sons will never become carriers.
In conclusion, I have outlined the main features of telomeres, there function in eukaryotic DNA replication , the action of telomerase and how shortening telomeres can have life threatening consequences. Another aspect that I found whilst researching is how sufferers of dyskeratosis congenita have a pre disposition to cancer, something which seems paradoxical due to cells lacking telomeres but however is extremely common. Unfortunately I didn’t have time to outline this in my essay but is a grave consequence of dyskeratosis congenita and furthermore shows how shortening telomeres can have even more catastrophic effects on humans than we may think.
Article Title:Telomeres, lifestyle, cancer, and ageing
Website Title: Telomeres, Lifestyle, cancer and ageing
Date Accessed: 18 Mar. 2018
In-Text: Masood A Shamas
Published: 14 Jan 2011
Author: Masood A. Shammas, Harvard (Dana Farber) Cancer Institute, Boston, Massachusetts, USA;
Article Title:Telomerase and the ageing process
Website Title: Telomerase and the ageing process
Accessed :18 Mar. 2018
In-Text: Hornsby 2007
Published: 30 Mar 2007
Author:Peter J. Hornsby, Department of Physiology and Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas;
Article Title: Dyskeratosis Congenita
Website Title: en.wikipedia.org
Accessed:18 Mar. 2018
In-Text: (En.wikipedia.org, 2018)
Published: 3 Mar. 2018
Author: Collective Authors
Article Title :Dyskeratosis Congenita
Website Title: Genetics Home Reference
Author: Genetics Reference
Accessed : 18 Mar. 2018
In- Text: (Reference, 2018)
Published : 13 Mar 2018
Article Title :The genetics of Dyskeratosis Congenita
Website Title: The genetics of Dyskeratosis Congenita
Accessed : 18 Mar. 2018
In- text: Philip J Mason and Monica Besslera, 2011
Published: December 2011
Author:Philip J Mason Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania
and Monica Besslera Internal Medicine, University of Pennsylvania
Article Title: TERC telomerase RNA component [Homo sapiens (human)] – Gene – NCBI
Article Title: ncbi.nlm.nih.gov
Accessed : 18 Mar. 2018
In- text : (Ncbi.nlm.nih.gov, 2018)
Published: 10 Mar 2018
Article title: Dyskeratosis Congenita – NORD (National Organisation for Rare Diseases)
Website Title: NORD (National Organization for Rare Diseases). (2018)
Accessed : 18 Mar. 2018
In-text: (NORD ( National Organisation for Rare Disorders),2018)
Author: NORD gratefully acknowledges the following for assistance in the preparation of this report: Monica Bessler, MD, PhD, Philip J. Mason, PhD, and David B. Wilson, MD, PhD, Departments of Internal Medicine and Pediatrics, Washington University School of Medicine.
Article Title: Dyskeratosis congenita mutations in the H/ACA domain of human telomerase RNA affect its assembly into a pre- RNP
Author: Trahan C, Dragon F
Published : February 2009
Date accessed: 18 Mar. 2018
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