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Saturday, May 15, 2021

Telomere - CSIR NET/ICMR/ DBT (Life Sciences)

Telomere

  • Telomeres are the terminal regions of the linear chromosome of eukaryotes (not is prokaryotes because of the circular chromosomes) composed of telomeric DNA and associated with specific proteins.

  • Telomeric DNA is associated with a large number of repetitive, strictly defined short nucleotide sequences or tandem repeats of 5'-TTAGGG-3' (vertebrates), TTTAGGG (terrestrial plants).


  • This sequence is usually repeated about 3,000 times and can reach up to 15,000 base pairs (bp) in length.
Telomere

Though telomeric proteins differ among different groups of organism they perform similar functions like;

  • telomere length regulations and protection against degradation.

For a long time, it was considered that telomeres did not code RNA molecule and thus proteins. Succeding, it was found that RNA is still transcribed from telomeres but it did not encode any protein. Further studies showed that this RNA plays an important role in;

  • telomere length regulations
  • chromatin reorganization during both development and cell differentiation.

Even though telomere does not encode protein. They also perform very important functions;

  • maintain the stability and functionality of the cellular genome.
  • help to organize each of our 46 (23 pairs) chromosomes in the nucleus of cells.
  • protects the end of the chromosome by forming a cap, much like the plastic tip on shoelaces. (If the telomeres were not there, the chromosome may end up sticking to other chromosomes).
  • protection of chromosomes from fusion with each other.
  • stabilization of broken chromosome ends.
  • attachment to the nuclear envelope.
  • influencing gene expression.
  • counting the quantity of cell division.
  • protection of the mRNA coding regions of the chromosome from the end replication problem.
  • participation in mitotic and meiotic chromosome segregation.

Telomeres dysfunction causes aging or cancer depending on the DNA damage response.

Factors that influence telomere function:

  • Telomerase
  • Telomeric chromatin
  • Shelterin complex


Telomerase:

Telomerase
  • It is a ribonucleoprotein called terminal transferase, that adds a species-dependent telomere repeat sequence to the 3' end of telomeres.

  • It is a two-partner enzyme, the reverse transcriptase catalytic subunit (TERT) and the RNA component (TERC), responsible for the maintenance of the length of telomeres by the addition of a G-rich repetitive sequence.

Telomeres need to be protected from a cell's DNA repair system because they have single-stranded overhangs, which "look like" damaged DNA. The overhang at the lagging strand end of the chromosome is due to incomplete end replication. The overhang at the leading strand end of the chromosome is generated by enzymes that cut away part of the DNA.


During each cell division cycle, telomeres shorten as a result of the incomplete replication of linear DNA molecules by conventional DNA polymerase. Telomerase compensates for telomere attrition through the addition of TTAGGG repeats by TERT onto the chromosome ends by using an associated RNA component as template TERC.


Shelterin Complex:

Shelterin Complex

  • Shelterin is a 6-subunit protein complex comprising TRF1, TRF2, POT1, TPP1, TIN2, RAP1, that associates with mammalian cells and allows cells to distinguish the natural ends of chromosomes from sites of DNA damage.

  • Shelterin binds telomeres through TRF1 and TRF2, which interact with the double-stranded (ds) telomeric DNA.

  • POT1 (POT1 & POT2 in the mouse) is associated with single-stranded (ss) telomeric DNA. 

  • POT1 is linked to TRF1 and TRF2 via an interaction between the POT1-binding protein TPP1 and TIN2, which binds both TRF1 and TRF2. 

  • RAP1 interacts solely with TRF2. It is dispensable for telomere capping but prevents telomere recombination and fragility. Thus RAP1 is not a telomere protective protein, in contrast to the rest of proteins. Hence, the role of RAP1 is telomerase regulation.

Function:

  • Shelterin function is crucial for telomere maintenance and genome integrity.
  • It protects telomeres from DNA damage signaling and DNA repair.
  • It promotes the semi-conservative replication of the telomeric DNA.
  • It regulates the telomerase-mediated maintenance of the telomeric DNA.


Telomere dysfunction and genome instability:

  • Genome instability is a prominent characteristic of most cancer types that have an essential role in tumorigenesis by accelerating the accumulation of genetic changes that are responsible for cancer cell evolution.

  • One of the important sources of genome instability is telomere shortening.

  • Telomere dysfunction can cause by a deficiency of telomerase and/or the shelterin proteins, either owing to the loss of the telomere protective structure, causes genome instability, and thereby affects tumorigenesis.

The molecular mechanism that related to telomere defects are:

  • Breakage fusion bridge cycles.
  • Defects in telomeric replication.
  • Susceptibility of telomeric DNA to genotoxic damage.
  • Cell cycle control and endoreduplication, replication of nuclear genome in the absence of mitosis, which leads to elevated nuclear gene content and polyploidy. E.g. Telomere shortening.


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