Cell senescence Flashcards
Define cell senescence
This is a programmed permanent cell growth arrest, with specific features and following define triggers.
why is cell senescence important?
- tumour suppression
–>preventscancer growth, preventing proliferation of damagin and cancerous cells.
-embryonic development
–>helps remove cells that are no longer needed threby contributing to the developmental process.
-wound healing
–> promotes tissue repair as they can secrete factors that stimulate tissue repair, contributing to healing process post injury
-ageing and age-related diseases
–>accumulation of senescent cells over time is associated with ageing and age-related diseases as senescent cells secrete factors including pro-inflammatory cytokines, proteases and growth factors that are collectively known as SASP (senescence associated secretatory phenotypes). this can cause tissue dysfucntion and chronic inflammation, thus contibute to ageing and age-related diseases like arthritis and neurodegeneration.
What are some of the triggers of cell senescence?
- Replicative senescence – many divisions.
- Oncogene overactivation- a gene that forces the cell to divide and too much of that can cause senescence. It goes straight it senescence without going through division.
- Genotoxic stresses. Oxidative damage, cancer drugs for example.(damage inflicted onto a cells genettic material that can be caused by external and internal factors like radiation, UV light, chemical agents, free radicals. these can cause DNA strand breaks, mustaions. therefore undergoes cellular arrest to prevent proliferation of damged cells.
- When there is DNA damage in the cell, sets up signal to repair the DNA, if doesn’t repair then the cell undergoes senescence
what are some of the morphological changes seen in senescent cells?
-large cells
-flat cells
-prominent nuclei
-mitochondiral dysfucntion threfore enhanced mitochondria mass
-cytoplasmic chnages appear more granular due to increased lysosomal content which is related to enahnced lysosomal beta-galactosidase activity
-edge of nucleus is often hard to see due to the loss of lamins and nuclear membrane proteins.
What are some of the cell properties/molecular markers seen in senescent cells?
-High B-galactosidase (Increased lysosomal content) Popular marker, blue stain, but not infallible.
-Expression of effectors (cell cycle inhibitors) like p16
-Elements of DNA damage signalling like 53BP1
-Increased ROS (reactive oxygen species) levels
-SASP- the senescence-associated secretory phenotype. [Implicated in ageing disorders.] Secretion of a battery of inflammation-related factors, e.g. IL6, IL8, IL1a (interleukins), MMPs (matrix metalloproteases), FGFs (fibroblast growth factors), VEGFs (vascular endothelial growth factors).
What are telomeres and what is different about the 3’end of the linear DNA?
telomeres are repetitive nucleotide sequences with a thousand repeat of a hexameter sequence -TTAGGG which do not encode for protein but play a critical role in protecting the ends of chromosomes from degradation and recognition as broken DNA by the cells repair system.
Telomeres: thousands of repeats of a hexamer sequence (TTAGGG) at chromosome ends.
* 3’ ends of linear DNA can’t be replicated normally, because an RNA primer has to bind beyond the part to be replicated. There is no “beyond” at the end.
* The enzyme telomerase is used instead to maintain telomere length.
what is telomerase and what are the different components of this enzyme and whichc condition has pathology whereby cells can divide indefinetely?
- Telomerase,is an enzyme that adds repetitive sequenced at the ends of eukaryotic chromosmes known as telomeres. crutial in maintaing length and integrity of chromosomes.
Telomerase uses RNA template (TERC)
to add new telomeric DNA repeats to the 3’ end of DNA strand. (compensates for loss of DNA at the end of every cell division due to the end-replication problem.
Telomerase has 2 main subunits componenets: -
-TERT: the protein component known as telomerase reverse transcriptase (the protein part).
-TERC (or TR): telomerase RNA component which serves as a RNA template for telomere extension.
telomerase activity occurs in cells that need to divide repeatedly siuch as stem cells, to maintain theri telomere length. many cancer cells reactivate telomerase contributing to their ability to divide indefinelty sustaining tumor growth.
what components of telomerase do gametes express? What do postnatal stem cells express? What do postnatal cells not express?
gametes express both TERT and TERC
postnatal stem cells express TERT
postnatal cells do not express TERT
how many telomeres is sufficient for replicative senescence to occur?
1-5 telomeres short
what is shelterin and what are its components?
shelterin is a protein coat/cap that stabilises and covers the loops of DNA to protect the telomere ends from DNA damage signalling processes from recogniing it as double-stranded breaks/ broken DNA which may lead to genetic instability.
how does senescence work (talk about the procedure and the changes that occur with the DNA end and sheltering)
normally the end of the telomeres are covered by shelterin
however as the telomeres get shortened the sheltering cap gets destabilised.
this gets recognised as a DNA damage and so signalling takes places whereby there is recruitment of p16, p21 and p53.
p53 signals to tell the cell to stop dividing.
what are p16 and p53 and what is their main mechanism of action?
p53 is a tumour suppressor
p16 and p21 are cdki that inhibit the s and m phase of cell senescence
what is etoposide?
it is a cancer drug that causes DNA damage to allow cells to undergo cell senescence.
what genetic abnormalities can cause cancer?
p16 defects
p53 defects
expression of TERT
how is cell senescence associated with age?
-the mean telomere length, which can be measured through white blood cells, fall with age.
