Ex2 L6 - Telomerase and Oncogenesis

Question 1

What three things can trigger senescence?

Answer 1

DNA damage, reaching the Hayflick limit, or mutations that promote too much cell cycling

Question 2

What is a nucleoprotein?

Answer 2

a small protein associated with DNA

Question 3

What are telomeres?

Answer 3

nucleoproteins that cap the end of each chromosome
- non coding
- consisting of proteins and repetitive hexameric nucleotide sequences of TTAGGG

Question 4

What is the function of a telomere?

Answer 4

protect against degradation, rearrangement, and fusion

Question 5

Telomeres are shortened during each…due to…

Answer 5

each somatic cell division due to the end replication problem

Question 6

Describe the end replication problem

Answer 6

When the strand is being copied into RNA, the polymerase has to start at a 3’ hydroxyl end. Since there is not a 3’ hydroxyl at the right end of the lagging strand, there will be a gap before polymerase starts forming the new strand. It will leave gaps periodically that are filled in by Okazaki fragments, but the initial end is not filled in because the primer doesn’t have anywhere else to attach. So, the end just gets cut off and we lose those nucleotides.

Question 7

How does a telomere solve the end replication problem?

Answer 7

When the end of the lagging strand gets cut off, it is really just the telomere sequence, not important DNA that is going to code for proteins

Question 8

What is telomerase?

Answer 8

reverse transcriptase enzyme that adds more hexameric sequences to elongate the 3’ end of telomeres (make them longer so that they don’t wear out as fast)

Question 9

Telomerase is active in…

Answer 9

stem cells, gametes, and cancer cells (but not somatic cells)

Question 10

Why is it important that the 3D structure of telomerase was discovered?

Answer 10

because structure of the enzyme relates to structure of the active site, and if we can figure that out then we can inhibit/activate the active site without needing actual telomerase

Question 11

Telomerase contains (many/one) subunit(s)

Answer 11

many subunits

Question 12

What is hTERT?

Answer 12

the human version of the catalytic subunit of telomerase

Question 13

Where is hTERT upregulated? Why?

Answer 13

stem cells - allow for self-renewal, no Hayflick limit

Question 14

Interestingly, somatic cells have —– but not ——

Answer 14

the other subunits of telomerase, but not the catalytic subunit

Question 15

Overexpression of hTERT in adults stem cells can cause…

Answer 15

them to develop and embryonic stem cell phenotype, aka become more pluripotent

Question 16

What is oncogenesis?

Answer 16

the process by which normal cells are transformed (phenotypically changed) into cancer cells

Question 17

Cancer cells want to…

Answer 17

• go through the cell cycle
• avoid senescence and apoptosis

Question 18

How can telomeres dysfunction, and what does it cause?

Answer 18

dysfunction:
- DNA damage
- chromosomal rearrangement
- fusion of chromosomes

leads to:
- DNA damage response
- mutated telomere gene leads to oncogenesis

Question 19

When stem cells telomeres eventually run out, what happens?

Answer 19

They also undergo senescence, resulting in stem cell exhaustion, and aging

Question 20

What are the M1 and M2 pathways?

Answer 20

As a telomere shortens, it reaches a point where it has a few short telomeres.
The healthy response is senescence (M1)
But, if they keep dividing and the telomeres get critically short, they now go down the crisis pathway (M2)
In the crisis pathway cells can either directly undergo apoptosis or undergo immortalization and become cancer cells (but that is rare)

Question 21

Immortalization/cancer is considered “rare,” but what is the occurrence?

Answer 21

1 in 10,000,000 (but we have trillions of cells, so that’s more than it seems like)

Question 22

Short telomeres are found in most…

Answer 22

cancers

Question 23

Short telomeres promote…

Answer 23

chromosomal instability (fusions or rearrangements)

Question 24

What is the greatest risk factor for cancer?

Answer 24

Age

Question 25

Telomerase activity is increased in —% of cancers

Answer 25

90%

Question 26

Is there one reason for increased telomerase activity, or many?

Answer 26

many - hTERT polymorphisms, Leptin/STAT2 pathway, or Ras activation are examples

Question 27

What do telomerase inhibitors do?

Answer 27

• encourage senescence and/or apoptosis in cells with short telomere length

Question 28

mTOR is important for…

Answer 28

telomerase activation

Question 29

Telomere length is related to…but not…

Answer 29

related to cancer risk
not related to lifespan

Question 30

How CAN we relate telomeres to lifespan?

Answer 30

the RATE of telomere shortening is most predictive of a SPECIES lifespan