lecture 2 Flashcards
(7 cards)
What is telomere theory?
Telomeres are very highly repeated DNA repeats at the end of chromosomes, differ between species
3’ overhangs get progressively shorter with each division
Once telomeres reach a certain point, the cell stops dividing & becomes senescent or undergoes apoptosis.
Number of divisions before this happens = the Hayflick limit
Replication needs to start with a primer (required for DNA polymerase to anneal to template strand). This is true for both lagging & leading strands, it’s just the lagging strand is re primed more often.. Once replication is completed, this primer is removed after successful replication. This leads to a slightly shorter complementary strand after each replication cycle.
Telomerase expressed at high levels in stem cells – add DNA back onto chromosomes
Allows stem cells to continue replicating for a lot longer than somatic cells
Most cells do not express telomerase
Highly active in stem cells, gametes, some cancer cells
Telomerase is essentially a very specialised reverse transcriptase
Telomeres shorten even in cells expressing telomerase (just slower)
Overexpressing telomerase in somatic cells can increase replicative lifespan, but causes tranformation
What is free radical theory?
Superoxide radical formation is an unavoidable aspect of oxygen based life and cellular metabolism
Oxidative damage can occur to proteins, nucleic acids or membranes (lipid peroxidation)
Nrf2 is a highly conserved activator of Gluathione (GSH) synthesis genes - how cells respond to free radicals
What is DNA damage theory?
different forms of DNA damage accumulate with age
Leads to increasing genome instability with age
Highly conserved sirtuins can act as DNA damage sensors to activate repair pathways
Alkalyted base – MGMT (Methyl Guanine Methyl Transferase)
Photoinduced dimers – PL (photolyase)
Photoinduced dimers – Nucleotide Excision repair
Single base pair lesions – Base excision repair
Mismatches – mismatch repair
DSB NHEJ or HR
Important genes are not distributed evenly throughout the genome
Depending on the position of DNA damage, and the cell type that damage happens in – the outcome can be very different
What are progeroid syndromes? give examples
are caused by mutations increasing DNA damage or in DNA repair pathway genes
Hutchinson-Gilford Syndrome
Lamin mutation (nuclear envelope)
Severe nuclear instability & v high rate of DNA damage
Life expectancy ~ 13 years
Cockayne syndrome
Mutations in CSA/CSB (NER repair enzymes)
Life expectancy 20-40 years
Werner Syndrome
WRN mutation (HR repair enzyme)
Life expectancy ~40 years
What is mitochondrial theory?
Integration of DNA damage & free radical theory
Places free radical / DNA damage to mitochondria foremost
Autophagy & Mitochondrial turnover also important (defective mitophagy = accumulation of defective mitochondria)
mtDNA damage accumulates with age
Mice with error prone mtDNA pol gamma age prematurely
mtDNA damage accumulates with age
Mice with knockout mitochondrial DNA polymerase
Mitochondrial mutations rapidly accumulate – die much sooner
What is the SASP phenotype?
SASP = Senescence associated secretory phenotype
Senescent cells change their microenvironment by secreting ECM modifiers and pro-inflammatory cytokines
A choice the cell can make after its telomeres are all worn out or it sees a certain amount of oxidative damage is to become senescent
As senescent cells build up they have an effect on the microenvironment around them – secrete substances
Can also encourage cells around to become senescent
What qualities would you say are most important when choosing a model organism to study ageing?
Lifespan (for full-life studies to be conducted), environmental conditions for survival (must be viable and economical)).
Life cycle of the organism - what would suit the experiment best
Genetic conservation with humans
Ageing phenotypic similarities
Similarities to human anatomy and physiology (as this is our final goal of study
Ability to monitor the healthspan of an organism as well as lifespan.
Using genetically heterogeneous organisms for ageing studies to reflect the heterogeneity of the human population.
