Telomeres

What are they?

• Telomeres are the ends of the linear chromosomes found in eukaryotes.

• Ends of DNA are vulnerable to damage from exonucleases so need to be protected.

• The cell also needs to know that these particular ends are NOT from a break (caused by exposure to radiation for example), which needs to be repaired by rejoining the two broken ends – this is supposed to be the actual end of a chromosome.

Importance

• Chromosome Stability: Telomeres protect the ends of chromosomes from degradation, fusion, and recombination. Without telomeres, the chromosome ends could be mistaken for damaged DNA, leading to DNA repair processes that could cause chromosomal rearrangements and genomic instability.

• Replication and Division: Telomeres facilitate complete replication of chromosome ends during cell division. Due to the end replication problem, the lagging strand is not fully replicated, and without telomeres, essential genetic material would be lost with each cell division.

What they contain

Telomeres consist of repetitive DNA sequences and associated proteins. The DNA component consists of a short repeating unit, usually a six-base-pair sequence, which varies between species. In humans, the repeat sequence is TTAGGG

Structure

Telomeric DNA adopts a unique structure referred to as a T-loop. In this structure, the single-stranded 3' overhang of the telomeric DNA can loop back and invade the double-stranded telomeric region, forming a looped structure that protects the chromosomal end

Maintenance

When too many of the repeats have been lost this triggers the cell to go into a quiet, non-dividing state called senescence, because the telomeres are no longer are coated in shelterin. This cell will die eventually and replaced by division of stem cell. This usually happens after about 50-60 divisions, which is called the Hayflick Limit. This serves as a protection against cancer, so the cell doesn’t divide too many times, which will gradually introduce more and more mutations due to replication error. In germline cells (the ones producing sperm or eggs) the process is different, the repeats lost in the last replication are replaced to maintain the T- and D-loop structure. The enzyme telomerase does this, which is a protein that also carries an RNA within it (hTR in humans) that acts a template to add more repeats after each division. The hTR sequence is complementary to the TTAGGG repeat

Telomerase is not

ACTIVE in the vast majority of somatic cells (only in some stem cells), so that’s why the telomeres gradually degrade in the soma

How does it repair the shortening?

Telomerase binds to the end of the TTAGGG strand using hTR, then synthesizes a new repeat, re-binds at the new end, synthesizes another repeat and so on. Once the 3’ overhang has been lengthened enough, primase can put a primer further away and regular DNA polymerase will make it double-stranded again, replacing the missing repeats and maintaining the telomere structure

More about telomeres

• Telomeres have up to 2,000 copies of a 6bp repeat, TTAGGG in vertebrates (sequence varies slightly among species), most of which is double-stranded, but the last 50 copies or so are single-stranded in a TTAGGG 3’ overhang.

• These repeats allow the 3’ overhang at the end to be tucked into an earlier part of the chromosome to form the D loop (D= displacement).

• This also creates a large loop of double-stranded DNA - the T-loop (T=telomere).

• The loop is also bound by multiple copies of a six-protein complex called Shelterin

  • The presence of shelterin coating the T-loop allows the cell to know that this is meant to be a chromosome end, and is not a double-stranded break that needs to be repaired