21st Feb - Senescence Flashcards
What is cellular senescence?
A terminal differentiation state in which metabolically active cells are permanently and irreversibly arrested with distinct morphological changes
What is the hayflick limit?
Normal human cells will divide a set number of times before they stop permanently
What is telomere shortening?
With each division telomeres shorten because duplication is not entirely complete
What are telomeres?
repetitive DNA sequences (TTAGGG) that cap the chromosomes and protect their ends from erosion
What is the end replication problem?
The inability of DNAP to work on 3’ ends leading to telomere shortening
How does telomere shortening cause cell cycle arrest?
When the telomeres become too short (<12.8 repeats of repetitive clusters) it leads to cell cycle arrest, senescence and apoptosis
What is the function of telomerase?
It can elongate the telomeres, refreshing the cell
What is SIPS?
Stress induced premature senescence
What triggers SIPS?
Detection of DNA damage signals
What are the main pathways for the activation of senescence?
Senescence signals –> p16 –| CDKs –| RB –| E2F –> senescence
Senescence signals –> p16 –| CDKs –| RB –> senescence
Senescence signals –> ARF –| HDM2 –| p53 –> p21 -> senescence
Senescence signals –> p53 –> p21 –> senescence
What are the markers of senescence?
Growth Arrest SA-Bgal DNA Damage Foci Heterochromatin foci p16INK4A Senescence associated secretory phenotype
How does senescence associated-Beta galactosidase show senescence?
Hydrolase enzyme that catalyzes the hydrolysis of β-galactosides into monosaccharides only in senescent cells, thus turning senescent cells blue
How are DNA damage foci created?
DNA damage response proteins (e.g. ATM) accumulate in the vicinity of a chromosomal ds DNA break creating subnuclear foci
What are heterochromatin foci?
Specialized domains of facultative heterochromatin that contribute to silencing of proliferation promoting genes e.g. E2AF
How can heterochromatin foci be visualized?
immunoflouresence staining