Telomeres in cancer and aging

Role of telomeres in ageing and cancer : 

Role of telomeres in ageing and cancer Madhu Aggarwal AK Chhabra Source: www.biology.utah.edu/posters2.php?id=20

Telomeres : 

Telomeres Muller coined the term telomere from Greek word telos “end” and meros “part”. Telomeres are repetitive DNA sequences located at the termini of linear chromosomes of most eukaryotic organisms, and a few prokaryotes. Telomeres are made of repeating sequences of TTAGGG on one strand of DNA bound to AATCCC on the other strand.

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Telomere length varies greatly between species. Usually composed of arrays of guanine-rich, six-to-eight base-pair-long repeats.

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physics.berkeley.edu scientificamerican.com Telomeres cap the ends of chromosomes

Historic background : 

Historic background Chromosome ends play important role in ensuring chromosome stability. This was first proposed by H.J. Muller in 1930s working with Drosophila melanogaster and Barbara McClintock in 1940 working with Zea mays. In 1965 Leonard Hayflick discovered a term “Hayflick Limit” that there was a limit to the number of cell divisions that a cell could give rise to. In 1972, James Watson gave the phenomenon "end replication problem".

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In 1973,Olovnikov proposed the telomere theory: namely, that somatic cells were limited because they cannot fully replicate their telomeres. In 1978, Blackburn and Gall discovered the telomeric DNA sequence of the ciliated protozoan Tetrahymena thermophila, (TTGGGG)n. In 1984 ,Carol W.Greider and Elizabeth Blackburn discovered Telomerase in the ciliate Tetrahymena. In 2009, Elizabeth Blackburn, Carol Greider, and Jack Szostak were awarded the 2009 Nobel Prize in Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.

Why do chromosomes have telomeres? : 

Why do chromosomes have telomeres? Without telomeres, the main part of the chromosome would get shorter each time a cell divides. Without telomeres, chromosome ends could fuse together and degrade the cell's genetic blueprint, making the cell malfunction, become cancerous or die. Because broken DNA is dangerous, a cell has the ability to sense and repair chromosome damage. Without telomeres, the ends of chromosomes would look like broken DNA, and the cell would try to fix something that wasn't broken.

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cbs.dtu.dk

Why do telomeres get shorter each time a cell divides? : 

Why do telomeres get shorter each time a cell divides? Before a cell can divide, the chromosomes within it are duplicated. A chromosome's two strands of DNA must unwind and separate. An enzyme (DNA polymerase) then starts to make two new strands of DNA to match each of the two unwound strands. When each new matching strand is completed, it is a bit shorter than the original strand.

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The rate of telomere loss in somatic cells is in the order of 50 to 200 nucleotides per somatic cell division. Telomeres are shorter in somatic cells compared to germ cells (about 9 kb of TTAGGG repeats in human sperm compared with 4 kb in somatic cells)

Functions of telomere : 

Functions of telomere Chromosome capping Replication and elongation of DNA Control of gene expression Nuclear organization

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highlighthealth.com greenpacks.org

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greenpacks.org

Telomere binding proteins : 

Telomere binding proteins The DNA component of telomeres is characterized in all vertebrates by tandem repeats of (TTAGGG/CCCTAA)n. Telomeric DNA typically ends in a single-strand G-rich overhang of between 50 and 300 nucleotides at the 3' end. In humans and mice, the length of telomere repeats at individual chromosome ends in individual cells is strikingly variable.

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Large number of proteins have been found to directly or indirectly associate with telomeric DNA. Some of these proteins are such as TRF1, TRF2, TIN2, TPP1, Rap1, and POT1. At the very distal end of the telomere this comlpex is implicated in the formation of a 300 bp single-stranded portion called as the T-Loop. POT1 and TRF2 bind to telomeric DNA in at least two different modes. The assembly of this complex relies on two bridging proteins that interact with each other.

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mun.ca

Telomerase : 

Telomerase Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomeric regions, which are found at the ends of eukaryotic chromosomes. As a result, every time the chromosome is copied only a couple telomeres are lost, which causes no damage to the organism. Telomerase is a reverse transcriptase that carries its own RNA molecule.

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www.uic.edu/.../bios100/f05pm/telomerase.jpg

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Telomerase is generally found only in : the cells of the germ line, including embryonic stem cells unicellular eukaryotes some “adult” stem cells and “progenitor" cells cancer cells.

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stemcells.nih.gov/info/scireport/appendixc.asp nblumenfeld.blogspot.com/2009/10/idea.html

Structure : 

Structure The protein composition of human telomerase was identified in 2007 by Scott Cohen and his team. It consists of two molecules each of TERT, TR or TERC, and DKC1. Human TERT gene (hTERT) is translated into a protein of 1132 amino acids. TERT has a 'mitten' structure that allows it to wrap around the chromosome to add single-stranded telomere repeats.

Functions : 

Functions TERC— provides an AAUCCC (in mammals) template to guide the insertion of TTAGGG. TERT— provides the catalytic action. Prevents telomere shortening. Prevents replicative senescence.

Telomere shortening : 

Telomere shortening Telomeres shorten with each cell division (S phase) The "end replication" problem: DNA replication is bidirectional DNA polymerases are unidirectional DNA polymerases must initiate replication from a primer Therefore: each round of DNA replication leaves 50-200 bp DNA unreplicated at the 3' end. Cells with telomeres that are 10-12 kb in length (average) divide 50-60 times. Telomeres are 4-6 kb [5-7 kb] in length (average). Cellular senescence is triggered when telomeres are on average 4-6 kb.

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users.rcn.com

Telomeres and DNA damage responses : 

Telomeres and DNA damage responses DNA damage signals are known to originate from short telomeres and contribute to p53 activation and the cellular responses to stress. The telomere binding protein TRF2 binds to ataxia telangiectasia mutated (ATM) kinase and can inhibit its function. As telomere length decreases with age, the amount of DNA damage signals originating from short telomeres is expected to increase. However, it has become clear that telomeres are directly responsible for sustained DNA damage signals in senescent cells.

Telomeres and Ageing : 

Telomeres and Ageing Aging can be defined as the progressive functional decline of tissue function that eventually results in mortality. Once the telomere shrinks to a certain level, the cell can no longer divide. It has been proposed that telomere shortening may be a molecular clock mechanism that counts the number of times a cell has divided and when telomeres are short, cellular senescence occurs.

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It is believed that shortened telomeres in mitotic (dividing) cells may be responsible for some of the changes we associate with normal aging. After a certain number of cell divisions, the telomeres would be so short as to somehow prevent the cell from further proliferation-putting it in a state called senescence.

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ARE TELOMERES THE KEY TO AGING AND CANCER?

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ARE TELOMERES THE KEY TO AGING AND CANCER?

Telomeres and Cancer : 

Telomeres and Cancer As a cell begins to become cancerous, it divides more often, and its telomeres become very short. When cells are approaching the Hayflick Limit in cell cultures, the time to senescence can be extended by the inactivation of the tumor suppressor proteins – TP53 and Retinoblastoma protein (pRb). Shortened telomeres have been found in many cancers, including pancreatic, bone, prostate, bladder, lung, kidney, head and neck.

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nature.com

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Cancer cells require a mechanism to maintain their telomeric DNA in order to continue dividing indefinitely (immortalization). The telomerase control gene has been mapped to 3p21. Telomerase activation has been observed in ~90% of all human tumors. ALT (Alternative Lengthening of Telomeres) , a non-conservative telomere lengthening pathway involving the transfer of telomere tandem repeats between sister chromatids. The exact mechanism behind telomere maintenance in the ALT pathway has not been elucidated.

Telomere function and human ageing related disease : 

Telomere function and human ageing related disease Dyskeratosis congenita (DC) is a disease of the bone marrow that can be caused by mutations in the dyskerin gene(DKC1). Patients with DC have- severe skin pigmentation leucoplakia (a white thickening of the oral mucosa) nail dystrophy bone marrow failure manifesting as abnormal. Mutations in TERT have been implicated in predisposing patients to aplastic anemia , a disorder in which the bone marrow fails to produce blood cells.

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Cri du cat syndrome (CdCS) is a complex disorder involving the loss of the distal portion of the short arm of chromosome 5. TERT is located in the deleted region, and loss of one copy of TERT has been contributing factor of this disease. Mutations in DKC1, hTERC, or hTERT cause defects in telomerase enzymatic activity that result in failure to elongate or maintain telomeres and induce progressive telomere shortening through haploinsufficiency mechanisms.

Summary : 

Summary Telomeres are repetitive DNA sequences located at the termini of linear chromosomes of most eukaryotic organisms, and a few prokaryotes. Telomeres play important role in ensuring chromosome stability. Without telomeres, the main part of the chromosome would get shorter each time a cell divides. Telomeres helps in chromosome capping, replication and elongation of DNA, control of gene expression and nuclear organization.

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Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomeric regions, which are found at the ends of eukaryotic chromosomes. Telomerase prevents telomere shortening and replicative senescence. Telomeres play important role in ageing and cancer. It is believed that shortened telomeres in mitotic (dividing) cells may be responsible for normal aging. Due to high telomerase activation in normal cells they may become cancerous hence leads to cancer.

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