ICL 8.2: Molecular Basis of Cancer/Cancer Cell Signaling Flashcards
In DCIS and PIN, the luminal epithelial cells have lost all detectable telomeric DNA, while the nearby normal myoepithelial cells or basal epithelial cells still carry strongly staining telomeres. The truncation of telomere in these cells is ostensibly due to the fact that
the expression of telomerase activity in these cells has not yet been turned on
these cell populations have passed through many more successive cell cycles than nearby normal cells
why do telomeres get shortened each cell cycle?
our replication machinery is not effective at copying sequences at the ends of chromosomes
this end-replication problem provides a molecular explanation for the observed shortening of telomeric DNA each time a normal human cell passes through a cell cycle
there’s also exonuclease within cells that slowly chew on the ends of telomeric DNA and may ultimately contribute far more to telomere erosion
This progressive erosion of telomeric DNA represents a simple molecular device that limits how many generations of descendant progeny a cell can spawn!!
what enzyme regenerates the telomere?
telomerase
what’s the structure of telomerase?
it’s composed of two subunits, the hTERT catalytic enzyme subunit and hTR RNA subunit
there’s also 5 other proteins required to form a functional holoenzyme
what does telomerase do?
it attaches to the 3’ end of the G-rich strand overhang, doing so in part through the hydrogen bonding of hTR to the last five nucleotides of the G-rich strand
Subsequently, by reverse transcription of sequences in the hTR subunit, hTERT is able to extend the G-rich strand by six nucleotides.
By repeating this process in hexanucleotide increments, the enzyme can extend the G-rich strand by hundreds, even thousands of nucleotides, doing so in a processive fashion
upon completion of this elongation, a conventional DNA polymerase can fill in the complementary strand
where is TERT expressed?
mainly confined to adult stem cells
telomeres are maintained by TERT
are telomeres longer or shorter in stem cells?
telomeres are longer in the stem cells than in their more differentiated progeny
explain aneuploidy and cancer
cancer cells are often aneuploid
the presence of abnormally structured chromosomes and changes in chro- mosome number provided the first clue, early in the twentieth century, that changes in cell genotype often accompany and perhaps cause the uncontrolled proliferation of malignant cells
how do cancer cells overcome their replicative capacity placed on them my telomere length?
cancer cells can overcome roadblock imposed by limited replicative capacity of cells by expressing telomerase
while the telomerase activity is low in most types of normal human cells, it is clearly detectable in 85-90 % of human tumor cells samples
importantly, suppression of telomerase activity results in loss of neoplastic growth
