GA Telomerase Prion 2024

Telomere and Telomerase

Overview

  • Telomeres: The protective ends of linear chromosomes, composed of repetitive DNA sequences.

  • Telomerase: An enzyme that elongates telomeres, counteracting their shortening during cell division.

The Nobel Prize in Physiology or Medicine 2009

  • Awarded for the discovery of telomeres and telomerase.

  • Key Figures:

    • Elizabeth H. Blackburn

    • Carol W. Greider

    • Jack W. Szostak

  • Contributions help elucidate how telomeres protect chromosomes.

Telomere Structure

Composition

  • Repetitive DNA sequences: TTAGGG (in vertebrates).

  • Specialized Proteins: Bind to telomeres, playing a role in their protection and maintenance.

Telomere Length in Various Species

Species

Reference Length (kb)

Mouse

40-100

Rat

20-100

Dog

12-23

Human (Somatic)

7-12

Human (Germ Cells)

9-13

The End Replication Problem

  • Definition: Each round of DNA replication shortens telomeres, known as the end replication problem.

  • Mechanism:

    • DNA polymerases require a 3' primer, leaving 50-200 bp unreplicated at the chromosome ends.

Telomere Shortening in Human Cells

  • The last RNA primer may leave 70-100 nucleotides unreplicated, leading to significant chromosome shortening.

  • Continuous shortening can lead to senescence or apoptosis if not compensated by telomerase activity.

Mechanisms of Telomere Shortening

Theoretical Models

  • Olovnikov's Model (1971): Initial theory explaining how telomeres shorten with incomplete replication.

  • New Model: Proposes G-overhangs at both ends and suggests overhang processing involves the MRN complex and nucleases.

Telomere Structure: T-loops and Shelterin Complex

  • T-loops: Structures formed by single-stranded telomere overhangs, protecting telomere ends from damage recognition.

  • Shelterin Complex: A six-protein complex, including TRF1, TRF2, TIN2, TPP1, RAP1, and POT1 that functions in telomere protection.

Cellular Responses to Telomere Dysfunction

DNA Damage Response (DDR)

  • Loss of shelterin leads to DNA damage responses, such as ATM activation and p53 pathway engagement.

  • Consequences: Potential telomere fusions and genomic instability.

Telomere and Cancer

  • Over 80-90% of cancer cells express telomerase which allows for replicative immortality despite telomere shortening.

  • Mechanisms of escape include ALT (alternative lengthening of telomeres) in some non-telomerase expressing cancers.

Telomere Dysfunction and Aging

  • Telomere shortening has been associated with aging and age-related diseases.

  • Critically short telomeres can trigger senescence or contribute to the pathogenesis of diverse diseases.

Prion Diseases Overview

  • Definition: Prions are infectious protein molecules that cause neurodegenerative diseases by inducing misfolding of normal proteins.

  • Symptoms: Include problems with movement coordination, dementia, paralysis, and nerve cell death.

  • Mechanisms: Prion propagation occurs through conformational changes and aggregation of proteins.

Types of Prion Diseases

  • Transmissible Spongiform Encephalopathies: Includes Creutzfeldt-Jakob Disease (CJD) and Bovine Spongiform Encephalopathy (BSE).

  • Transmission: Can occur through infection, inheritance, or sporadic mutations.

Advances in Prion Understanding

  • Research has focused on the cellular function of normal prion proteins and their role in neuroprotection.

  • Genetic modifications and understanding mutogens offer pathways to control prion diseases.