Ex2 L6 - Telomerase and Oncogenesis Flashcards
What three things can trigger senescence?
DNA damage, reaching the Hayflick limit, or mutations that promote too much cell cycling
What is a nucleoprotein?
a small protein associated with DNA
What are telomeres?
noncoding nucleoproteins that cap the end of each chromosome
- consisting of proteins and repetitive hexameric nucleotide sequences of TTAGGG
What is the function of a telomere?
protect against degradation, rearrangement, and fusion
Telomeres are shortened during each…due to…
each somatic cell division due to the end replication problem
Describe the end replication problem
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. The gap can’t be filled in by Okazaki fragments because the primer doesn’t have anywhere else to attach. So, the end just gets cut off and we lose those nucleotides.
How does a telomere solve the end replication problem?
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
What is telomerase?
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)
Telomerase is active in…
stem cells, gametes, and cancer cells (but not somatic cells)
Why is it important that the 3D structure of telomerase was discovered?
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
Telomerase contains (many/one) subunit(s)
many subunits
What is hTERT?
the human version of the catalytic subunit of telomerase
Where is hTERT upregulated? Why?
stem cells - allow for self-renewal, no Hayflick limit
Interestingly, somatic cells have —– but not ——
the other subunits of telomerase, but not the catalytic subunit (hTERT)
Overexpression of hTERT in adults stem cells can cause…
them to develop and embryonic stem cell phenotype, aka become more pluripotent
What is oncogenesis?
the process by which normal cells are transformed (phenotypically changed) into cancer cells (can be due to dysfunction of hTERT)
Cancer cells want to…
- go through the cell cycle
- avoid senescence and apoptosis
What does telomere dysfunction cause?
causes:
- DNA damage
- chromosomal rearrangement
- fusion of chromosomes
leads to:
- DNA damage response
- mutated p53 leads to oncogenesis
When stem cells telomeres eventually run out, what happens?
They also undergo senescence, resulting in stem cell exhaustion, and aging
What are the M1 and M2 pathways?
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)
Immortalization/cancer is considered “rare,” but what is the occurrence?
1 in 10,000,000 (but we have trillions of cells, so that’s more than it seems like)
Short telomeres are found in most…
cancers
Short telomeres promote…
chromosomal instability (fusions or rearrangements)
What is the greatest risk factor for cancer?
Age
Telomerase activity is increased in —% of cancers
90%
Is there one reason for increased telomerase activity, or many?
many - hTERT polymorphisms, Leptin/STAT2 pathway, or Ras activation are examples
What do telomerase inhibitors do?
- encourage senescence and/or apoptosis in cells with short telomere length
mTOR is important for…
telomerase activation
Telomere length is related to…but not…
related to cancer risk
not related to lifespan
How CAN we relate telomeres to lifespan?
the RATE of telomere shortening is most predictive of a SPECIES lifespan
