WK1:Enabling Replicative Immortality

What is the fourth hallmark of cancer?

Enabling Replicative Immortality – the ability of cancer cells to divide indefinitely without entering senescence or crisis.

What is the Hayflick limit?

The limited capacity of cultured normal human cells to divide – approximately 20-70 times – after which they enter senescence. Described by Leonard Hayflick.

Who discovered the Hayflick limit and approximately when?

Leonard Hayflick described replicative cellular senescence approximately 40 years ago (published 1965). This phenomenon is now known as the Hayflick limit.

What is cellular senescence?

A state of permanent cell cycle arrest where cells stop dividing but remain viable. Normal cells enter senescence after reaching the Hayflick limit or in response to stress.

What are telomeres?

Protective caps at the ends of chromosomes consisting of repetitive DNA hexameric TTAGGG nucleotide repeats and a protein complex called shelterin. They prevent chromosomes from fraying or linking to each other.

What is the "shoelace analogy" for telomeres?

Telomeres are like plastic caps on shoelaces – they prevent the ends of chromosomes from fraying. When telomeres become too short the ends become frayed like a shoelace missing its cap.

What is the telomere DNA sequence in humans?

TTAGGG (hexameric repeats repeated thousands of times at chromosome ends).

What is shelterin?

The protein complex that binds to telomeric DNA to protect chromosome ends and regulate telomere length.

What happens to telomeres each time a cell divides?

Each time a cell divides the telomeres get shorter and shorter because DNA polymerase cannot fully replicate the 3' ends of chromosomes.

What happens when telomeres become critically short?

Critically short telomeres trigger a DNA damage signal. This leads to either senescence (permanent cell cycle arrest) or death (crisis).

What is crisis in the context of telomeres?

A state of massive cell death that occurs when telomeres become critically short. Characterized by karyotypic disarray and end-to-end chromosomal fusions. This is a protective anti-cancer mechanism.

What is telomerase?

A cellular reverse transcriptase enzyme that adds DNA sequences (TTAGGG) onto telomere ends to prevent shortening. It counteracts the progressive telomere erosion that occurs during cell division.

In what percentage of malignant tumours is telomerase detected?

Telomerase is detected in approximately 85-90% of all malignant tumours.

How do cancer cells achieve replicative immortality?

Cancer cells upregulate or reactivate telomerase to maintain telomere length AND they bypass cell cycle checkpoint genes (e.g. p53 p21 p16 Rb) that would otherwise trigger senescence or apoptosis.

What happens when telomerase is upregulated in a cell?

Telomerase adds TTAGGG repeats to telomere ends preventing progressive shortening. This allows cells to bypass crisis and continue dividing indefinitely – IMMORTALISATION

Who won the Nobel Prize in Physiology or Medicine in 2009 and for what?

Elizabeth Blackburn Carol Greider and Jack Szostak won the 2009 Nobel Prize for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.

What are telomerase promoter mutations?

Mutations in the promoter region of the telomerase gene (TERT). They are the most common point mutations in cancer and lead to increased telomerase expression.

How does telomerase activity support cancer progression through genomic instability?

By preventing crisis telomerase allows damaged cells to survive and divide. These cells pass on mutations to daughter cells leading to accumulation of genetic alterations and genomic instability which drives cancer progression.

Why is telomerase considered a therapeutic target for cancer?

Because 85-90% of cancers express telomerase while most normal cells do not. Inhibiting telomerase could selectively induce crisis and death in cancer cells without harming normal cells.

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

No – as of this lecture there are no approved anti-telomerase therapies yet. It remains an active area of research.

What is the relationship between telomerase and cell cycle checkpoint genes?

To achieve immortality cancer cells must BOTH upregulate telomerase AND bypass checkpoint genes (p53 p21 p16 Rb). Telomerase alone is not sufficient if checkpoints are intact.

What is the normal protective function of telomere shortening?

Telomere shortening acts as a counting mechanism that limits cell divisions. When telomeres become critically short cells die (crisis) – this prevents unlimited proliferation and protects against cancer.

Complete this sentence from slide 8: "When telomeres become critically shortened this triggers a DNA damage signal where cells can die (______) or become ______."

Crisis / senescent

Why is the Enabling Replicative Immortality hallmark relevant to ageing as well as cancer?

Telomere shortening contributes to cellular ageing and age-related diseases. Understanding telomeres and telomerase could lead to therapies for both cancer (inhibit telomerase) and ageing (activate telomerase).