Telomere is the repeating structure found at the end of chromosomes. Its primary function is the 'capping function' i.e. to protect the chromosome ends from DNA degradation. Additionally, it also prevents the recombination with free ended DNA ends and is crucial in DNA repair mechanisms. Telomeric repeats are lost with each round of cell replication.
The telomeres of sufficient length are vital to maintaining genetic integrity. They can be considered as the intrinsic biological clock which regulates the lifespan of the cell i.e. they provide limits on the number of replications the cell can go through.
Telomerase is the enzyme responsible for maintenance of telomeric entity which is an RNA dependent DNA polymerase. Telomerase is also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres.
The telomeric constitution includes three known entities:
- Tandem repeats of DNA sequence
The telomeric DNA of mammals contains TTAGGG repeats and their complementary sequences. The size of telomere in human is about 5 kb to 15 kb. A key feature of the telomere end in all organisms is a 39 single-stranded G-rich overhang (Makarov et al., 1997; McElligott and Wellinger, 1997).
Mammalian G-rich overhangs are 30-500 nucleotides long (Chai et al., 2005) and are generated by the removal of the RNA primer from the terminal Okazaki fragment on the lagging strand, as well as by post-replicative processing events that involve nucleases performing 39 resections on both newly synthesized strands. In other organisms such as worms 59 single-stranded C-rich overhangs have been detected (Raices et al., 2008) and patterns can occur transiently in some human cancer cells (Oganesian and Karlseder, 2011).
- Specific set of binding proteins
Telomere binding proteins are a specific set of proteins which bind the telomeric DNA. The proteins are specific and diversified with the species. Mammals contain a multi-subunit protein complex called the Telomere binding protein complex (also termed as shelterin) which is composed of the following subunit proteins.
TRF1 or TERF1 - Telomeric repeat binding factor - 1
TRF2 or TERF2 - Telomeric repeat binding factor - 2
TIN2 or TINF2 - TRF1 interacting nuclear factor 2
RAP1 or TERF2IP - TERF2 interacting protein
TPP1 or ACD - adrenocortical dysplasia protein homolog
POT1 - protection of telomeres 1
TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA and provide high specificity to the shelterin complex. Both TRF1 and TRF2 bind the telomeric repeat sequences in the duplex region of the genome in vivo. POT1 is yet another DNA binding protein. TIN2, RAP1, TPP1 are adaptor proteins influencing signalling complexes.
Different other telomere-associated factors like DNA damage factors, nucleases, helicases and DNA replication proteins are also shown to be recruited as accessory factors for the shelterin complex.
Telomere-binding proteins function to generate a T-loop, which is a specialized loop structure to cap the telomeric ends. Telomerase activity is regulated by the protection of telomeres 1 (POT1).
a non-coding RNA transcript
The transcripts of telomeres, termed as TERRA (telomeric repeat-containing RNA), a lncRNA (long noncoding RNAs) have been identified as the third entity of the telomere nucleoprotein complex functioning in the regulation of telomerase activity and heterochromatin formation at the chromosome ends. Emerging evidence indicates that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability.
TERRA transcription is mediated by RNA polymerase II and is initiated from the sub-telomeric regions that are found near chromosome ends.
Other Important Telomere functions:
- Telomeres prevent the cell from treating chromosome ends as broken chromosomes.
- They help to ensure equal distribution of genetic material into each gamete at meiosis.
- They are involved in regulating the expression of highly variable subtelomeric genes in response to environmental changes.
Sources:
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