Metabolism and Genome Integrity

Question 1

What are the most common features of accelerated aging?

Answer 1

Disruption in metabolism and genome integrity.

Question 2

What type of gene is age-1/daf-23 and what affect does it have in C . elegans?

Answer 2

It is a recessive, loss of function gene which limits adult life.

Question 3

What does a complete loss of function in daf-23/age-1 cause in C. elegans?

Answer 3

Constitutive production of dauerlarvae.

Question 4

What does partial loss of function of daf-23/age-1 lead to in C. elegans?

Answer 4

Normal adults which live longer. They display some of the long living phenotype of the dauerlarvae without actually becoming one.

Question 5

What is dauer formation regulated by?

Answer 5

The insulin signalling pathway

Question 6

What does insulin do?

Answer 6

Promotes glucose uptake from the blood and conversion of glucose to glycogen.
Increased fatty acid synthesis.
Increases esterification of fatty acids.

Question 7

What two receptors regulate insulin signalling in mammals?

Answer 7

The insulin receptor and the insulin-like growth factor 1 receptor

Question 8

If calories are restricted, leading to no insulin, will Daf-16 be turned on or off? What is the effect on dauerlarvae development?

Answer 8

Daf-16 is turned on if insulin is low, leading to dauer development

Question 9

Why is daf-16 required for age-1/daf-23 longevity?

Answer 9

Daf-16 mutants block age-1/daf-23

Question 10

True or false: The mutant alleles which cause longevity in C. elegans are all partial loss of function.

Answer 10

True

Question 11

What is the equivalent to Daf-16 in humans?

Answer 11

FOXO (Forkhead transcription factor)

Question 12

A downstream target of daf-16 are the chaperones. What do these promote?

Answer 12

Proteostasis

Question 13

What does partial calorific restriction promote in C. elegans?

Answer 13

Longevity

Question 14

What do mutants which block insulin signalling in C. elegans promote?

Answer 14

Dauerlarvae formation

Question 15

What do mutants which partially block insulin signalling promote in C. elegans?

Answer 15

Longevity

Question 16

In what other species do the same genes present in C. elegans promote longevity?

Answer 16

Drosophila - starved flies live longer.

Question 17

What molecule is known as the “Guardian of the Genome”?

Answer 17

p53

Question 18

What is the name given to the terminal stress activated defence mechanism which is regulated by p53?

Answer 18

Cellular senescence

Question 19

What is p53 and what does it regulate?

Answer 19

It is a transcription factor which regulates gene expression.

Question 20

What percentage of human cancers have a mutation which inactivates p53? Where does this mutation usually occur?

Answer 20

50% of all human cancers have a mutation which inactivates p53. This is usually found in its DNA binding domain.

Question 21

What is p53’s response to moderate genome damage?

Answer 21

Induces DNA repair allowing for a return to normal.

Question 22

What is p53’s response to severe genome damage such as telomere dysfunction?

Answer 22

Senescene

Question 23

What is p53’s response to severe genome damage along with hyperproliferation?

Answer 23

Apoptosis

Question 24

Name four things which p53 acts in response to

Answer 24

1) DNA damage
2) Telomere dysfunction
3) Oncogene activation
4) Reactive oxygen species

Question 25

What is cellular senescence?

Answer 25

A stable, and usually irreversible, cell cycle arrest.

Question 26

What does cellular senescence defend against?

Answer 26

It protects organisms against potentially dangerous cells such as pre-cancerous cells. It has a tumour suppressor function.

Question 27

What are some triggers of cellular senescence?

Answer 27

Response to DNA damage, telomere loss, loss of nuclear integrity, and other forms of cellular damage.

Question 28

During aging, what can cellular senescence contribute to?

Answer 28

The depletion of stem cells.

Question 29

Accumulation of senescent cells is a main hallmark, and possible major cause, of what?

Answer 29

Ageing

Question 30

What are telomeres?

Answer 30

Repetitive DNA sequences at the end of chromosomes.

Question 31

Why do the end of chromosomes shorten with every replication cycle?

Answer 31

Telomere repeats are lost as DNA polymerase is incapable of replicating all the way to the end of linear chromosomes.

Question 32

What happens once all telomere repeats are lost?

Answer 32

The shortening of chromosome ends continues, eventually causing gene deletion.

Question 33

There is a clear correlation between number of cell culture doublings and what feature of the organism?

Answer 33

Life expectancy

Question 34

What is the Hayflick limit?

Answer 34

The Hayflick limit, discovered in the 1960s, describes the finite number of times cells can divide in cell culture before they have severe telomere shortening or loss. This is when they become senescent (induced by p53).

Question 35

What direction does DNA polymerase work and what does it require to initiate polymerisation?

Answer 35

DNA polymerase can only work in the 5' to 3' direction and required a primer to initiate polymerisation. It is initiated by RNA primers which then degrade, leaving single stranded DNA.

Question 36

What does telomerase do? What two subunits make it up?

Answer 36

It is an enzyme which grows telomeres and is composed of reverse transcriptase and telomerase RNA.

Question 37

Do germline, embryonic and adult stem cells have telomerase?

Answer 37

Germline cells have telomerase and can grow telomeres. Embryonic stem cells have telomerase and can be cultured indefinitely. Most adult stem cells have some telomerase but usually less than germline stem cells.

Question 38

What effect does accumulation of senescent cells have on stem cells?

Answer 38

Causes a loss of stem cells