Telomere Dynamics

Telomere Dynamics

Telomeres are repetitive DNA sequences (TTAGGG in humans) at chromosome ends that protect genetic information. They solve the "end replication problem" but shorten with each cell division, acting as a molecular clock for cellular aging.

The End Replication Problem

DNA polymerase requires RNA primers and can only synthesize in the 5'→3' direction. After replication, the RNA primer at the lagging strand's 5' end is removed, leaving a gap that cannot be filled. This causes 50-200 bp loss per division in human cells.

Shelterin Complex

• TRF1 & TRF2: Bind double-stranded telomeric DNA
• POT1: Binds single-stranded 3' overhang
• TPP1: Links POT1 to TIN2, recruits telomerase
• TIN2: Central hub connecting TRF1, TRF2, and TPP1
• RAP1: Associates with TRF2, regulates telomere length

T-Loop Structure

The 3' single-stranded overhang folds back and invades the double-stranded telomeric DNA, forming a protective loop structure. This hides the chromosome end from being recognized as a DNA break.

Telomerase

Telomerase is a ribonucleoprotein with reverse transcriptase activity (TERT) and an RNA template (TERC). It adds TTAGGG repeats to the 3' end. Active in stem cells and germ cells, but repressed in most somatic cells. Reactivation occurs in ~90% of cancers.

Cellular Senescence

When telomeres become critically short (~2-4 kb), the DNA damage response is activated. Cells enter replicative senescence (Hayflick limit, ~50-70 divisions for human fibroblasts). Further shortening leads to crisis and cell death or, rarely, immortalization.