Telomere week 6

What is the "End Replication Problem"?

During DNA replication the lagging strand is synthesized discontinuously using RNA primers. The final primer at the very end of the chromosome cannot be replaced with DNA leading to a progressive shortening of the chromosome with each cell division.

What is Telomerase?

A specialized reverse transcriptase enzyme that solves the end-replication problem. It consists of two main subunits: TERT (the catalytic reverse transcriptase subunit) and TERC (an RNA template complementary to the telomere repeat sequence). It extends the G-rich 3' overhang allowing DNA polymerase to fill in the lagging strand.

What is the T-loop?

A protective cap structure formed at the end of the chromosome where the 3' single-stranded G-rich overhang folds back and invades the double-stranded telomeric DNA creating a displacement loop. This structure hides the chromosome end preventing it from being recognized as a DNA break.

What is the role of TRF2?

Telomeric Repeat-binding Factor 2; a key protein in the shelterin complex that is essential for the formation and stability of the T-loop structure. Loss of TRF2 function "uncaps" the telomere which is immediately recognized as a double-strand break activating the ATM/p53 DNA damage response.

What is Replicative Senescence (the Hayflick Limit)?

The finite number of divisions a normal human cell can undergo before it permanently exits the cell cycle. This is primarily caused by the progressive shortening of telomeres which eventually triggers a DNA damage response (via p53 and Rb pathways). It acts as a natural tumor suppressor mechanism.

What is Crisis?

A state of extreme genomic instability that occurs if a cell bypasses senescence (e.g., by losing p53/Rb function) and continues to divide with critically short, uncapped telomeres. This leads to rampant end-to-end chromosome fusions and Breakage-Fusion-Bridge (BFB) cycles, causing massive cell death and mutations.

What are Breakage-Fusion-Bridge (BFB) Cycles

A process during crisis where an uncapped chromosome fuses with another which creates a dicentric chromosome (two centromeres). During anaphase the spindle poles pull the centromeres apart which randomly breaks the chromosome. The new broken ends are uncapped and can fuse again in the next cycle driving genomic chaos (amplifications. deletions).

How do cancer cells achieve immortality?

To escape crisis and divide indefinitely a cell must stabilize its telomeres. This is achieved in ~90% of human cancers by reactivating the expression of TERT (telomerase). The remaining ~10% use a mechanism called ALT (Alternative Lengthening of Telomeres) which is based on homologous recombination.

How does telomere dysfunction act as both a tumor suppressor and promoter?

Tumor Suppressor (Early Event): Telomere shortening in normal cells activates senescence which is a powerful barrier to proliferation. Tumor Promoter (Late Event): If senescence is bypassed the subsequent telomere-driven crisis and BFB cycles can generate the massive number of mutations and genomic rearrangements needed for malignant transformation.

Telomeres

Terminal structures on linear chromosomes composed of thousands of TTAGGG repeats; they protect chromosome ends from degradation and fusion.

End Replication Problem

The inability of DNA polymerase to fully replicate the very ends of the lagging strand leading to progressive shortening of chromosomes with each cell division.

Telomerase

A specialized reverse transcriptase enzyme that solves the end-replication problem by extending the G-rich 3' overhang.

TERT (Telomerase Reverse Transcriptase)

The catalytic protein subunit of telomerase.

TERC (Telomerase RNA Component)

The RNA subunit of telomerase that provides the template (complementary to TTAGGG) for TERT to synthesize new telomeric DNA.

T-loop (Terminal Loop)

A protective cap structure formed when the 3' single-stranded G-rich overhang folds back and invades the double-stranded telomeric DNA creating a displacement loop.

Shelterin Complex

A complex of six proteins (TRF1. TRF2. POT1. etc.) that binds to the TTAGGG repeats and is crucial for forming and maintaining the protective T-loop structure.

TRF2 (Telomeric Repeat-binding Factor 2)

A key component of the shelterin complex essential for T-loop stability; its loss "uncaps" the telomere which is recognized as a DNA Double-Strand Break (DSB).

Telomere Uncapping (DSB response)

Loss of TRF2 function leads to uncapping which activates the ATM/p53 DNA damage response mimicking a DSB. Loss of POT1 leads to a single-strand break (SSB) and an ATR response.

Replicative Senescence (Hayflick Limit)

The permanent cell cycle exit that occurs in normal human cells after a finite number of divisions triggered when telomeres shorten to a critical length. This is a tumor-suppressive mechanism.

Crisis

A state of massive genomic instability and rampant cell death that occurs if a cell bypasses senescence (e.g., by losing p53/Rb) and continues to divide with critically short, uncapped telomeres.

Breakage-Fusion-Bridge (BFB) Cycles

The process occurring during crisis where uncapped chromosomes fuse end-to-end to form dicentric chromosomes; these are pulled apart during mitosis breaking randomly and leading to massive genomic chaos (amplifications/deletions).

Telomerase Reactivation (Cancer)

The mechanism used by ~90% of human cancers to achieve immortality involving the re-expression of the catalytic TERT subunit to stabilize telomere length.

ALT (Alternative Lengthening of Telomeres)

A telomere maintenance mechanism used by the remaining ~10% of cancers; it relies on homologous recombination to copy telomeric DNA from one chromosome to another.

Telomere Function (Dual Role)

Tumor Suppressor (early event: shortening → senescence) and Tumor Promoter (late event: bypassing senescence → crisis → genomic chaos).