Cell Determination & Cell Senescence

Question 1

what is cell determination?

Answer 1

process whereby cell fate becomes stable and is followed by cell differentiation

Question 2

what is a master gene regulator?

Answer 2

a transcription factor that regulates many or all of the genes specifically expressed in a cell type.

Question 3

what is cell determination caused by?

Answer 3

• by inductive signals from neighbouring cells
• one group of cells influences the development of other cells
• pioneer factors/master regulators & cofactors play important role in cell-fate decision making

Question 4

what is cell senescence?

Answer 4

the irreversible cell-cycle arrest mechanism where cells cease to divide

Question 5

why does cellular senescence occur?

Answer 5

• as a response to excessive extra/intracellular stress

- strongly implicated in symptoms of ageing but also important defence against cancer

Question 6

what is the hayflick limit?

Answer 6

the maximum number of times a cell can divide before reaching senescence

-all cells have except for cancer cells

Question 7

what types of changes does senescence apply to cells

Answer 7

-morphological, biochemical, chromatin changes in cell

Question 8

what are the morphological changes that occur in a cell?

Answer 8

• larger flat cells
• prominent nuclei
• nuclear lamina degradation
• vacuolised
• chromatin reorganisation

Question 9

what are the 2 molecular markers of the cell

Answer 9

β-galactosidase and protein p16

Question 10

what are the products of biochemical and molecular changes associated with?

Answer 10

inflammation, proliferation and changes to the intracellular matrix

Question 11

what is the p53 pathway?

Answer 11

the main way to control senescence

Question 12

what are the main factors of senescence?

Answer 12

telomere attribution

Question 13

what are telomeres?

Answer 13

regions at the end of the chromosomes composed of the TTTAGG DNA sequence

Question 14

unstable chromosomes are due to what?

Answer 14

loss of telomeres and risk resulting in flanking genes

Question 15

when is replicative senescence triggered?

Answer 15

when the telomeres get short, 1-5 telomeres

Question 16

what is telomerase?

Answer 16

an enzyme that replicates telomeric DNA by reverse transcription

Question 17

how does telomerase work?

Answer 17

they reverse transcribe telomeric headers from RNA using RNA (TERC) and it’s protein component (TERT)

Question 18

what are TERT and TERC

Answer 18

• TERT: telomerase reverse transcriptase (the protein part, = catalytic subunit).
• TERC (or TR): telomerase RNA component

Question 19

how does p53 work?

Answer 19

the ATM proteins scan the DNA for damage and activate the p53 which activates p21 which codes for proteins that arrest cell division at G1

Question 20

what are the 2 stages in which telomerase elongates telomeric DNA?

Answer 20

1) synthesis

2) translocation

Question 21

explain the process of how telomerase elongates telomeric DNA

Answer 21

• telomeric DNA w overhanging 3’ end
• newly synthesised lagging strand binds to telomerase RNA
• 3’ end of the leading strand elongated by one repeat unit as an extension of the leading strand
• the RNA primer is removed
• telomeric DNA extended

Question 22

what are the mechanisms of cell senescence?

Answer 22

• the telomeres shorten
• the DNA damage signal phosphorylates p53 (a tumour suppressor), activating it
• the p53 stimulates the expression of p21 (a growth inhibitor)
• P21 inhibits CDK 1/2/4/6
• that means that there is no phosphorylation of pRB, meaning that it remains bound to E2F, blocking transcription, thus effectively arresting cell division.
• radiation, oxidative stress or DNA damage occurs.
• this activates p53 (and that continues down the same path as before) and p16
• P16inhibits CDK 4/6
• that also continues down the same path as before.

Question 23

why are germ line cells immortal?

Answer 23

they express TERT so they maintain full length telomeres

Question 24

what is the relationship between cancer and telomeres?

Answer 24

cancer cells activate telomeres which leads to the uncontrollable replication

• 90% of all cancer cells express TERT = infinite divisions
• advanced cancer cells surpass senescence

Question 25

what are some abnormalities that lead to defective senescence and immortality of the cell?

Answer 25

• expression of TERT
• p53 defects
• p16 defects

Question 26

what is the relationship between telomeres and ageing?

Answer 26

shortening of telomeres cause old age

Question 27

what is the evidence that telomere shortening is the cause of old age?

Answer 27

• p16 and associated proteins expressed increasingly in ageing tissues (leading to senescence)
• telomere length varies between people but genetically linked to age at death
• defective genes for telomerase subunits give symptoms w premature ageing and death
• p16 locus genetically linked w human senile defects like TII diabetes, cardiovascular diseases and cancer

Question 28

do embryonic stem cells express TERT?

Answer 28

yes, this means they are immortal

Question 29

do telomeres in somatic stem cells shorten?

Answer 29

yes, but they shorten less than in somatic cells