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A telomere is a region of DNA found at the ends of chromosomes and commonly found in eukaryotes. It is made up of repetitive nukleotide Sequences and works with specific proteins to protect the chromosomal DNA from progressive degradation. Telomeres prevent double-strand break breaks from being misidentified by DNA repair and keep the genetic material stable.

Discovery

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The idea of telomeres was first suggested in 1938 by Hermann Joseph Muller, who studied fruit flies named Drosophila melanogaster, and in 1939 by Barbara McClintock, who worked with maize. [1] Muller noticed that the ends of chromosomes had a protective cap, which they named telomeres.[2]

Later, in the 1970s,Alexey Olovnikov discovered that chromosomes cannot fully replicate their ends, leading to the "end replication problem." Expanding on this idea and considering Leonard Hayflick's concept of limited somatic cell division, Olovnikov suggested that each time a cell divides, DNA sequences are gradually lost, until a critical threshold is reached, at which point cell division stops. According to his marginotomy theory, the DNA sequences at telomere ends are made up of tandem repeats that form a buffer, controlling the number of divisions a cell clone can undergo. He also predicted that a specialized DNA polymerase, originally named tandem-DNA-polymerase, could extend telomeres in immortal tissues such as germline cells, cancer cells, and stem cells. His hypothesis further suggested that organisms with circular genomes, like bacteria, do not face the end replication problem and therefore do not experience aging. [3][4][5]

Olovnikov proposed that an enzyme might be activated to prevent the shortening of DNA ends with each cell division. This phenomenon can happen in some cells such as: cells of vegetatively propagated organisms, germline cells, and in immortal cell populations like most cancer cell lines.[6][7]

Between 1975 and 1977, Elizabeth Blackburn and Joseph G. Gall, discovered the unique structure of telomeres, where simple repeated DNA sequences form the ends of chromosomes. In 2009, Blackburn, Carol Greider, and Jack Szostak received Nobel Prize in Physiology or Medicine for their discovery of how both telomeres and enzyme telomerase protect chromosomes.[8][9][10]

Structure and function

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End replication problem

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DNA replication, DNA polymerase faces a challenge DNA polymerase cannot replicate the 3' ends of the parent strands due to its unidirectional synthesis, where it only adds nucleotides to the 3'-end (3'-5' synthesis). On the leading strand (3'-5' direction), DNA-polymerase replicates continuously until reaching the strand's end, where the RNA primer is replaced with DNA. On the lagging strand (3'-5' direction), continuous replication is not possible, requiring discontinuous replication with repeated primer synthesis further along the strand.

The last primer on the lagging strand is near the 3'-end of the template, not exactly at the end. It was initially thought that DNA polymerase couldn't replicate the last segment, but it is now understood that the primer sits 70-100 nucleotides from the end, correlating with the shortening of DNA in human cells by 50-100 base pair after each cell division.[11].[12]

If coding sequences were lost, crucial genetic information could be lost. Telomeres, non-coding repetitive sequences at chromosome ends, protect coding sequences by serving as buffers. They "cap" the ends and degrade over time during replication. Since most prokaryotes (like bacteria) have circular chromosomes, they do not face the "end replication problem". Some bacteria like Streptomyces, Agrobacterium, and Borrelia, have linear chromosomes with telomeres, which are structurally and functionally different from eukaryotic telomeres. These bacterial telomeres are composed of proteins at chromosome ends or hairpin loops of single-stranded DNA. [13] In many species, the sequence repeats are enriched in guanine, e.g. TTAGGG in vertebrates,[14]

Telomere ends and shelterin

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At the 3'-end of the telomere, a 300-base pair overhang can invade the double-stranded region, forming a T-loop structure. This loop, similar to a knot, stabilizes the telomere and prevents it from being recognized as a DNA break by repair machinery. Without this protection, non-homologous end joining could cause chromosomal fusion. The T-loop is maintained by the shelterin complex, which in humans includes six proteins: TRF1, TRF2,TIN2, POT1, TPP1, and RAP1.[13] In many species, telomere repeats are rich in guanine (e.g., TTAGGG in vertebrates)[14], facilitating the formation of G-quadruplexes, a unique DNA structure involving non-Watson-Crick base pairing. Some species, like ciliates, may form G-quadruplexes instead of T-loops at their 3'-overhangs. G-quadruplexes can hinder enzymes like DNA polymerases and are believed to play a role in regulating replication and transcription.[15]

Telomerase

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Many organisms have telomerase, a ribonucleoprotein enzyme that adds repetitive nucleotide sequences to DNA ends, replenishing the telomere "cap" without using ATP.[16] In most multicellular eukaryotes, telomerase is active only in germ cells, some stem cells (like embryonic stem cells), and certain white blood cells. Somatic cell nuclear transfer Cite error: A <ref> tag is missing the closing </ref> (see the help page).can reactivate telomerase and reset telomeres to an embryonic state. The gradual shortening of telomeres in somatic cells may contribute to senescence[17] and in the prevention of cancer.[18][19]

Length

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Telomere length varies significantly across species, ranging from about 300 base pairs in yeast to several kilobases in humans.[20] They typically consist of guanine-rich, six- to eight-base pair repeats. Eukaryotic telomeres end with a 3′ single-stranded DNA overhang, ranging from 75 to 300 bases, crucial for telomere maintenance and capping. Various proteins bind to both single- and double-stranded telomere DNA to aid in these processes.[21] Telomeres form T-loops, where the single-stranded DNA curls into a circle, stabilized by telomere-binding proteins.[22] At the T-loop's end, the single-stranded telomere DNA base pairs with double-stranded DNA, creating a triple-stranded structure called a displacement loop (D-loop).[23]

Shortening

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Oxidative damage

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In vitro studies show that oxidative stress damages telomeres, significantly influencing their shortening in vivo. While reactive oxygen species (ROS) cause DNA damage in various ways, it is unclear whether telomeres are inherently more vulnerable or have reduced DNA repair activity. Despite agreement on these findings, concerns remain about measurement flaws, including species and tissue dependency. [24][25] Population studies suggest a link between anti-oxidant intake and telomere length. The LIBCSP study found that women with shorter telomeres, low beta carotene, vitamin C or E intake had a higher breast cancer risk, highlighting the role of oxidative stress in cancer development.[26] [27]

Association with aging

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While telomeres shorten over a lifetime, the telomere shortening rate, not length, determines a species' lifespan.[28] Very short telomeres trigger a DNA damage response and cellular senescence.[28]

In experimental animals, telomere shortening is linked to aging, mortality, and related diseases. While lifestyle factors like smoking, diet, and exercise affect lifespan, longer telomeres may be associated with greater life expectancy in old age.[8]

References

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  1. ^ Varela, E.; Blasco, M. A. (March 2010). "2009 Nobel Prize in Physiology or Medicine: telomeres and telomerase". Oncogene. 29 (11): 1561–1565. doi:10.1038/onc.2010.15. ISSN 1476-5594. PMID 20237481. S2CID 11726588.
  2. ^ Muller, H.J. (1938). The Remaking of Chromosomes. Woods Hole. pp. 181–198.
  3. ^ Olovnikov, A. M. (1971). "[Principle of marginotomy in template synthesis of polynucleotides]". Doklady Akademii Nauk SSSR. 201 (6): 1496–1499. ISSN 0002-3264. PMID 5158754.
  4. ^ Olovnikov, A. M. (1973-09-14). "A theory of marginotomy: The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon". Journal of Theoretical Biology. 41 (1): 181–190. Bibcode:1973JThBi..41..181O. doi:10.1016/0022-5193(73)90198-7. ISSN 0022-5193. PMID 4754905.
  5. ^ Olovnikov, A. M. (1996). "Telomeres, telomerase, and aging: origin of the theory". Experimental Gerontology. 31 (4): 443–448. doi:10.1016/0531-5565(96)00005-8. ISSN 0531-5565. PMID 9415101. S2CID 26381790.
  6. ^ Olovnikov, I. A. (2023). "[«He always talked about something else…» Alexey Matveyevich Olovnikov and his unusual science.]". Advances in Gerontology = Uspekhi Gerontologii. 36 (2): 162–167. doi:10.34922/AE.2023.36.2.001. ISSN 1561-9125. PMID 37356090.
  7. ^ "Library Index". olovnikov.com. Retrieved 2024-10-13.
  8. ^ a b Blackburn EH, Gall JG (March 1978). "A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena". Journal of Molecular Biology. 120 (1): 33–53. doi:10.1016/0022-2836(78)90294-2. PMID 642006.
  9. ^ "Elizabeth H. Blackburn, Carol W. Greider, Jack W. Szostak: The Nobel Prize in Physiology or Medicine 2009". Nobel Foundation. 2009-10-05. Retrieved 2012-06-12.
  10. ^ Lipps HJ, Rhodes D (August 2009). "G-quadruplex structures: in vivo evidence and function". Trends in Cell Biology. 19 (8): 414–22. doi:10.1016/j.tcb.2009.05.002. PMID 19589679.
  11. ^ Olovnikov AM (September 1973). "A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon". Journal of Theoretical Biology. 41 (1): 181–90. Bibcode:1973JThBi..41..181O. doi:10.1016/0022-5193(73)90198-7. PMID 4754905.
  12. ^ Chow TT, Zhao Y, Mak SS, Shay JW, Wright WE (June 2012). "Early and late steps in telomere overhang processing in normal human cells: the position of the final RNA primer drives telomere shortening". Genes & Development. 26 (11): 1167–1178. doi:10.1101/gad.187211.112. PMC 3371406. PMID 22661228.
  13. ^ a b Martínez P, Blasco MA (October 2010). "Role of shelterin in cancer and aging". Aging Cell. 9 (5): 653–66. doi:10.1111/j.1474-9726.2010.00596.x. PMID 20569239.
  14. ^ a b Meyne J, Ratliff RL, Moyzis RK (September 1989). "Conservation of the human telomere sequence (TTAGGG)n among vertebrates". Proceedings of the National Academy of Sciences of the United States of America. 86 (18): 7049–53. Bibcode:1989PNAS...86.7049M. doi:10.1073/pnas.86.18.7049. PMC 297991. PMID 2780561.
  15. ^ Lipps HJ, Rhodes D (August 2009). "G-quadruplex structures: in vivo evidence and function". Trends in Cell Biology. 19 (8): 414–22. doi:10.1016/j.tcb.2009.05.002. PMID 19589679.
  16. ^ Mender I, Shay JW (November 2015). "Telomerase Repeated Amplification Protocol (TRAP)". Bio-Protocol. 5 (22): e1657. doi:10.21769/bioprotoc.1657. PMC 4863463. PMID 27182535.
  17. ^ Whittemore, Kurt; Vera, Elsa; Martínez-Nevado, Eva; Sanpera, Carola; Blasco, Maria A. (2019). "Telomere shortening rate predicts species life span". Proceedings of the National Academy of Sciences. 116 (30): 15122–15127. Bibcode:2019PNAS..11615122W. doi:10.1073/pnas.1902452116. ISSN 0027-8424. PMC 6660761. PMID 31285335.
  18. ^ Shay JW, Wright WE (May 2005). "Senescence and immortalization: role of telomeres and telomerase". Carcinogenesis. 26 (5): 867–74. doi:10.1093/carcin/bgh296. PMID 15471900.
  19. ^ Wai LK (July 2004). "Telomeres, telomerase, and tumorigenesis--a review". MedGenMed. 6 (3): 19. PMC 1435592. PMID 15520642.
  20. ^ Shampay J, Szostak JW, Blackburn EH (1984). "DNA sequences of telomeres maintained in yeast". Nature. 310 (5973): 154–7. Bibcode:1984Natur.310..154S. doi:10.1038/310154a0. PMID 6330571. S2CID 4360698.
  21. ^ Williams TL, Levy DL, Maki-Yonekura S, Yonekura K, Blackburn EH (November 2010). "Characterization of the yeast telomere nucleoprotein core: Rap1 binds independently to each recognition site". The Journal of Biological Chemistry. 285 (46): 35814–24. doi:10.1074/jbc.M110.170167. PMC 2975205. PMID 20826803.
  22. ^ Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T (May 1999). "Mammalian telomeres end in a large duplex loop". Cell. 97 (4): 503–14. doi:10.1016/S0092-8674(00)80760-6. PMID 10338214. S2CID 721901.
  23. ^ Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S (2006). "Quadruplex DNA: sequence, topology and structure". Nucleic Acids Research. 34 (19): 5402–15. doi:10.1093/nar/gkl655. PMC 1636468. PMID 17012276.
  24. ^ Barnes R, Fouquerel E, Opresko P (2019). "The impact of oxidative DNA damage and stress on telomere homeostasis". Mechanisms of Ageing and Development. 177: 37–45. doi:10.1016/j.mad.2018.03.013. PMC 6162185. PMID 29604323.
  25. ^ Reichert S, Stier A (December 2017). "Does oxidative stress shorten telomeres in vivo? A review". Biology Letters. 13 (12): 20170463. doi:10.1098/rsbl.2017.0463. PMC 5746531. PMID 29212750.
  26. ^ Shen J, Gammon MD, Terry MB, Wang Q, Bradshaw P, Teitelbaum SL, et al. (April 2009). "Telomere length, oxidative damage, antioxidants and breast cancer risk". International Journal of Cancer. 124 (7): 1637–43. doi:10.1002/ijc.24105. PMC 2727686. PMID 19089916.
  27. ^ Mathur MB, Epel E, Kind S, Desai M, Parks CG, Sandler DP, Khazeni N (May 2016). "Perceived stress and telomere length: A systematic review, meta-analysis, and methodologic considerations for advancing the field". Brain, Behavior, and Immunity. 54: 158–169. doi:10.1016/j.bbi.2016.02.002. PMC 5590630. PMID 26853993.
  28. ^ a b Cite error: The named reference pmid35165420 was invoked but never defined (see the help page).
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