Telomeres and Their Functions

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Questions and Answers

What is the primary role of Ang1 in relation to vascular integrity?

Inhibiting TIE-2 phosphorylation

Promoting endothelial cell migration

Stabilizing vascular integrity (correct)

Increasing angiogenic switch occurrence

Which of the following statements about Ang2 is accurate?

It primarily increases TIE-2 phosphorylation.

It has no effect on vascular integrity.

It is responsible for promoting endothelial cell migration. (correct)

It enhances the stability of vascular structures.

What defines the angiogenic switch in tumor growth?

A balance favoring pro-angiogenic factors (correct)

A state of increased anti-angiogenic factors

A complete cessation of angiogenesis

A decrease in existing blood vessel formation

Which of the following molecules is considered a pro-angiogenic factor?

VEGF Signup and view all the answers

In the context of cancer treatment, which of the following approaches has been proposed to manipulate tumor angiogenesis?

Introducing anti-angiogenic compounds Signup and view all the answers

What is one of the primary functions of telomeres in eukaryotic chromosomes?

Prevent fusion of ends with other DNA molecules Signup and view all the answers

In humans, what is the characteristic repeat sequence found in telomeres?

TTAGGG Signup and view all the answers

What happens to telomeres in normal somatic cells as they age?

They shorten gradually Signup and view all the answers

What model describes the structure formed by G-rich telomeric sequences in solution?

G-quartet Signup and view all the answers

What role does telomerase play in DNA replication?

It extends the 3’ overhang of telomeres Signup and view all the answers

What is the Hayflick limit related to in human cells?

The predictable number of cell divisions before replicative senescence Signup and view all the answers

What is a characteristic feature of senescent cells in culture?

Flattening and expression of specific marker genes Signup and view all the answers

What method is used to study the location and structure of telomeres?

Fluorescent in situ hybridization (FISH) Signup and view all the answers

What is the primary consequence of telomere dysfunction in cells during continuous divisions?

Induction of chromosomal rearrangements Signup and view all the answers

Which mechanism primarily leads to the bypass of replicative senescence in murine cells?

Deletion of p16/p19 INK4A locus Signup and view all the answers

What is the role of p19ARF in the cellular response to stress?

Stabilizing p53 Signup and view all the answers

Which of the following proteins is upregulated during human cell replicative senescence?

p16INK4A Signup and view all the answers

How does the dysfunction of telomeres contribute to genomic instability in epithelial carcinogenesis?

Via breakage-fusion-bridge cycles Signup and view all the answers

What effect does the activation of telomerase have in carcinoma-in-situ stages?

It leads to chromosomal stability Signup and view all the answers

What happens to cells experiencing prolonged culture that reach the Hayflick limit?

They induce checkpoint effectors Signup and view all the answers

In the context of cancer, what does the term 'angiogenesis' refer to?

Development of new blood vessels Signup and view all the answers

What defines the role of the lymphatic system in relation to cancer?

It drains excess fluid and immune cells Signup and view all the answers

What is the purpose of the breakage-fusion-bridge (BFB) cycle in cancer cells?

It results in new mutations Signup and view all the answers

What happens if p53 checkpoints are overcome or lost in cells?

They can continuously divide with unstable telomeres Signup and view all the answers

Which cellular component is NOT primarily involved in the development of angiogenesis?

Myocytes Signup and view all the answers

What is indicated by high levels of genomic instability in mTERC, p53 double null mice?

They avoid activating DNA-damage induced apoptosis Signup and view all the answers

Which signaling molecules are majorly involved during angiogenesis?

VEGF, Ang1, and Ang2 Signup and view all the answers

Study Notes

Telomeres

Telomeres are the ends of chromosomes in eukaryotic cells.
They have three primary functions:
- Prevent chromosomal degradation.
- Prevent fusion of chromosome ends.
- Facilitate faithful replication of linear DNA ends.
Telomeres have a unique, short repetitive sequence.
- Human telomeres contain the repeat sequence TTAGGG, highly conserved in vertebrates.
- This repeat sequence is repeated hundreds to thousands of times.
- Telomere length shortens with age in normal somatic cells.
- Cancerous and germ cells maintain telomere length.
The 3' end of a telomere is a single-stranded overhang.
- Overhang length varies between organisms.
- Human overhangs are typically 125-275 bases.
- It is G-rich, allowing for non-Watson-Crick base-pairing. G-quartet formation and T-loop formation stabilize the telomere.
Telomerase is essential for telomere replication.
- It's composed of an RNA template (TERC) and a reverse transcriptase catalytic subunit (TERT).
- Telomerase uses the G-rich strand as a template to synthesize new DNA at the 3' end.
- DNA polymerase fills the lagging strand. Repeating these processes lengthens telomeres.
Telomerase activity is often elevated in cancer cells.

Replicative Senescence

In dividing human cells, telomeres gradually shorten.
- This leads to cellular senescence, an irreversible loss of the ability to divide in culture.
- Senescent cells undergo morphological changes, express specific marker genes (like SA-β-galactosidase), and display altered behaviors (SASP).
- Shortened telomeres can activate cellular senescence despite growth factors and glucose being present.
Signal from shortened telomeres activate Rb, p53, and p16Ink4A, inducing replicative senescence.
Cancer cells can bypass senescence through the expression of the TERT subunit or through alternative mechanisms.
In mouse cells, senescence bypass is linked to altered p16/p19 INK4A functioning indirectly through p19ARF stabilization of p53.
Senescence can also be induced by cellular stress, activating p53 and Rb/p15 pathways, even independent of telomere erosion, by uncovering telomere ends alone.

Telomere Dysfunction and Cancer

Prolonged culture of human cells leads to the Hayflick limit, activating checkpoints like Rb, p53, and p16InkA and triggering replicative senescence.
- Bypassing these checkpoints leads to crisis, with chromosomal instability due to breakage-fusion-bridge cycles. This creates amplified, deleted regions generating large amounts of damage and new mutations.
Telomere dysfunction can activate apoptosis.
- If apoptosis is bypassed, cancer cells may reactivate telomerase (majority of cases) or use a mechanism called ALT to stabilize telomeres, which allows cells to grow.
Ongoing epithelial turnover during aging, coupled with somatic mutations disabling oncogenic checkpoints, can lead to telomere shortening and genomic instability, contributing to carcinogenesis.
This instability and mutations associated with telomere attrition can contribute to cancer progression.
P53 mutation can attenuate growth arrest and apoptotic phenotypes, accelerating tumor development.

Angiogenesis

Angiogenesis is the formation of new blood vessels from existing ones.
Key cell types involved in angiogenesis are vascular endothelial cells, pericytes, and smooth muscle cells.
Angiogenesis is crucial for tumor growth and delivery of anti-cancer therapeutics.
Factors like VEGF, Ang1, Ang2, and PDGF influence these processes.
VEGF is a major regulator of angiogenesis.
Ang1 promotes vascular integrity by recruiting pericytes.
Ang2 destabilizes the vascular structure.
Pro-angiogenic factors (e.g., VEGF) and anti-angiogenic factors counteract each other. The balance between these factors determines the outcome.
Statins and other molecules can inhibit angiogenesis.

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Description

This quiz covers the essential aspects of telomeres, including their structure, functions, and significance in cellular biology. You will learn about the repetitive sequences, telomere length dynamics, and the roles of telomerase in telomere replication. Test your knowledge on eukaryotic cell chromosome ends and their impact on aging and cancer.