enabling replicative immortality

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What is the fourth hallmark of cancer?

Enabling Replicative Immortality – cancer cells can divide forever without getting old or dying.

What is the Hayflick limit?

Normal human cells can only divide a limited number of times (about 20 to 70 divisions) before they stop. This is called the Hayflick limit.

Who discovered the Hayflick limit?

Leonard Hayflick – about 40 years ago.

What is senescence?

Senescence is a state where cells stop dividing permanently but stay alive. It is one of the barriers that prevents unlimited growth.

What is crisis?

Crisis is cell death that occurs when telomeres become too short. It is the final barrier to unlimited division. Cells die when they reach crisis.

What are telomeres?

Telomeres are protective caps at the ends of chromosomes. They are made of repetitive DNA (sequence TTAGGG) and a protein complex called shelterin.

What is the shoelace analogy for telomeres?

Telomeres are like plastic tips on shoelaces. They stop the ends from fraying. Each time a cell divides, the tips get shorter.

What happens to telomeres each time a normal cell divides?

Telomeres get shorter and shorter. The cell loses about 50 to 100 base pairs of telomere DNA with each division.

What happens when telomeres become critically short?

The cell detects damaged DNA (because short telomeres look like broken DNA). The cell then either enters senescence (stops dividing) or dies (crisis).

What is the end-replication problem?

DNA polymerase cannot fully copy the very ends of chromosomes. This means the telomeres get slightly shorter with each round of DNA replication.

What is telomerase?

Telomerase is an enzyme that adds TTAGGG DNA sequences back onto telomeres to keep them long. It is a type of enzyme called reverse transcriptase.

How does telomerase work?

Telomerase carries a small piece of RNA that matches the TTAGGG sequence. It uses this RNA as a template to add new TTAGGG repeats to the ends of telomeres.

In what percentage of cancers is telomerase detected?

Approximately 85% to 90% of all malignant tumours have telomerase activity.

How do cancer cells achieve replicative immortality?

Cancer cells do two things: 1) They upregulate telomerase to maintain telomere length. 2) They bypass cell cycle checkpoint genes (like p53, p21, p16, and Rb).

What happens if a cell has telomerase but still has working checkpoints?

The cell may still stop dividing. p53 and Rb can still arrest the cell cycle even if telomeres are long. Both telomerase AND broken checkpoints are needed for immortality.

What are telomerase promoter mutations?

These are mutations in the DNA region that controls telomerase expression. They turn on telomerase when it is normally off. They are the most common point mutations in cancer.

What happens when telomerase is activated in a cell that already has other mutations?

The cell can survive and divide forever. It passes on its existing mutations to daughter cells. This leads to more mutations accumulating over time (genomic instability).

Why does telomerase activation lead to genomic instability?

Because damaged cells that should die in crisis instead survive. They keep dividing and each division creates new mutations. Eventually the cell becomes more aggressive and malignant.

Who won the Nobel Prize in 2009 for discovering telomeres and telomerase?

Elizabeth Blackburn, Carol Greider, and Jack Szostak.

Why is telomerase considered a therapeutic target for cancer?

Because 85-90% of cancers express telomerase but most normal cells do not. Inhibiting telomerase would cause cancer cells to lose their telomeres and die, while normal cells would be spared.

Are there any approved anti-telomerase therapies for cancer yet?

No – as of this lecture, no anti-telomerase therapies have been approved. They are still being researched in clinical trials.

What is the normal protective function of telomere shortening?

Telomere shortening acts as a counting mechanism. It limits how many times a cell can divide. This prevents damaged cells from dividing forever and becoming cancerous.

What two things must cancer cells do to become immortal?

1) They must upregulate telomerase (or activate the ALT pathway) to keep telomeres long. 2) They must bypass checkpoint genes like p53, p21, p16, and Rb.

What is the ALT pathway?

ALT stands for Alternative Lengthening of Telomeres. It is a recombination-based mechanism that maintains telomeres without using telomerase. About 10-15% of cancers use ALT.

Why is telomerase relevant to ageing as well as cancer?

Too little telomerase = telomeres shorten faster = cells senesce earlier = ageing. Too much telomerase = cells become immortal = cancer risk. There is a delicate balance.

What happens in normal cells with no telomerase?

Telomeres shorten with each division. After many divisions (20-70), telomeres become critically short. The cell enters senescence or crisis and stops dividing.

What is the difference between senescence and crisis?

Senescence = cell stops dividing but stays alive (reversible in some cases). Crisis = cell dies (irreversible). Both are barriers to unlimited growth.

What is the role of p53 in the response to short telomeres?

p53 detects short telomeres as DNA damage. It then either arrests the cell cycle (to prevent division) or triggers apoptosis (to kill the cell). Cancer cells must mutate p53 to bypass this.

What does telomerase add to telomeres?

Telomerase adds TTAGGG DNA repeats to the ends of telomeres. This prevents the progressive shortening that normally happens during cell division.

Complete the sentence from Slide 8: "When telomeres become critically shortened this triggers a DNA damage signal where cells can die (______) or become ______.",crisis / senescent

What is shelterin?

Shelterin is the protein complex that binds to telomeres. It protects the ends of chromosomes and regulates telomere length. It also prevents the cell from mistaking telomeres for broken DNA.

What is the difference between normal cells and cancer cells regarding telomeres?

Normal cells = telomeres shorten with each division, eventually stop dividing. Cancer cells = telomeres stay long (via telomerase or ALT), divide forever.