WK1: Enabling Replicative Immortality

What is the fourth hallmark of cancer?

Enabling replicative immortality — cancer cells acquire the ability to divide indefinitely, bypassing normal cellular aging

What is the Hayflick limit?

The maximum number of times a normal human cell can divide (approximately 20–70 times) before entering senescence.

Who discovered the Hayflick limit?

Leonard Hayflick in the 1960s.

What is cellular senescence?

A state in which cells remain alive but stop dividing, often triggered by telomere shortening or stress.

What are telomeres?

Repetitive nucleotide sequences (TTAGGG) and associated proteins at the ends of chromosomes that protect them from degradation and fusion.

What is the function of telomeres?

They prevent chromosome ends from being recognized as DNA damage, avoid end-to-end fusion, and maintain genomic stability.

What happens to telomeres with each cell division?

They shorten due to the end-replication problem

What is the “crisis point” in telomere biology?

When telomeres become critically short, leading to genomic instability, senescence, or apoptosis.

What is the shelterin complex?

A protein complex that protects telomeres and regulates telomere length and function.

What is telomerase?

A ribonucleoprotein enzyme that adds telomeric repeats (TTAGGG) to chromosome ends, counteracting telomere shortening

What are the two main components of telomerase?

TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component)

In which normal cells is telomerase active?

Stem cells, germ cells, and certain immune cells.

How is telomerase activity in most normal somatic cells?

It is repressed or absent.

How is telomerase activity in cancer cells?

It is reactivated or upregulated in approximately 85–90% of cancers, enabling unlimited division.

How do cancer cells achieve replicative immortality?

By reactivating telomerase (or, less commonly, using ALT—alternative lengthening of telomeres) to maintain telomere length

What are telomerase promoter mutations?

Mutations in the promoter region of the TERT gene that increase telomerase expression; they are among the most common point mutations in cancer.

How does telomere maintenance contribute to genomic instability?

It allows cells with DNA damage and mutations to continue dividing, accumulating further genetic alterations.

Why is telomerase a potential therapeutic target in cancer?

Because it is active in most cancer cells but not in most normal cells, offering a potential selective target

Why are there no approved anti-telomerase therapies yet?

Due to challenges in drug delivery, selectivity, and the slow effect of telomere shortening on tumor growth.

How might inhibiting telomerase affect cancer cells?

It would cause telomere shortening, leading to senescence or apoptosis after several cell divisions.

How does replicative immortality relate to sustaining proliferative signaling?

mmortality allows cancer cells to respond continuously to growth signals without entering senescence.

How does it relate to resisting cell death?

By maintaining telomeres, cancer cells avoid apoptosis triggered by critically short telomeres.

How does it relate to genomic instability?

Telomere dysfunction can cause chromosomal fusion and breakage, driving instability; maintaining telomeres allows unstable cells to survive and proliferate.