"when a telomere becomes dysfunctional due to telomere shortening or removal of telomere proteins, a full DNA damage checkpoint is activated via ATM or ATR protein kinases, members of the PI-3 protein kinase-like family. Activation of the checkpoint leads to accumulation of γH2AX and other DNA repair proteins" (Jacob & Price in 2007 in the journal of "Molecular and Cellular Biology")

by the way, it is not G1/S transition checkpoint, but intra-S-phase checkpoint (ATM- and/or ATR-mediated DNA damage checkpoint), that is, right after G1/S transition. This is crucial, since when a cell passes G1/S transition, it has to divide anyways, because it is the most important decision making step. Getting stuck in intra-S-phase checkpoint makes step pause the cell cycle, and try to solve problem.

Also, abscence of telomere regions makes chromosomal endings "sticky". This is consequence of removal of telomeric repeats. As you recall, telomere repeats are important for capping the ending of the chromosome. And telomere shortening happens because of the abscence of 3'OH group of leading strand to fill in the missing nucleotides to replace RNA primer. Now, if telomerase is dysfunctional, these ends would not be able to cap, and since there are 46 chromosomes in humans, then there are 46 pairs of one strand of telomere repeat. Since these repeats are not capped, they can bind to each other and form complexes. Those sticky complexes are the main problem at intra-S-phase checkpoint. They are impossible to divide into two, and thus they may cause aneuploidy if intra-S-phase checkpoint would not work.

Mechanism of how telomere works you can see in this paper:

http://www.nature.com/nature/journal/v467/n7312/full/nature09353.html

"Failure to maintain proper telomere length or structure can result in chromosome rearrangements, cell apoptosis, senescence, or permanent inhibition of cell proliferation. Failure to properly maintain telomere ends can result in uncapped telomeres that activate PIKK such as the ATM protein" (http://www.nature.com/jid/journal/v124/n4/full/5602773a.html)

And all the papers point on "p53-dependent apoptotic response" in abscence of telomeres. That is, I couldn't find a direct indormation on the mechanism of apoptosis in p53-independent pathway.

If p53 is absent, and telomerases are inactive, then cell would continue on replicating, till reaching the end of the telomeric region. But after that, it would stop at G1/S checkpoint of cell cycle, and cease to continue. Such cells just die as in "programmed death" for normal cells, and do apoptosis. Necrosis is not applicable for this situation.

You are right. Shortening of the telomeres is sensed as DNA damage which might lead to apoptosis. But in addition cells which have undergone progressive shortening of telomeres can also enter a senescence. This cellular senescence is characterized by metabolically active cells which don't divide. Whether a cell enters apoptosis or senescence depends on various factors like e.g. cell type, genetic profilge. Human fibroblasts e.g. become senescent when the their telomeres are shortened.

Thanks Elbay and Tobias. Elbay, do you known what are the pathway involved in apoptosis in this case?

I don't remember the details right now. But, from what I recall, the G1/S transition requires preparation for division, such as translation of many copies of replication proteins for S phase and etc. Here it was also the case for preparation of DNA for S phase, where it required the availability of telomere region to continue division. Inability to check any of the points from G1/S phase transition makes the cells to stop division, and stay still. This is done to provide time for cell to repair the problem (in this case, elongate the telomere region). But since this is not applicable, cell would promote FADD (fas-associated death domain) and similar apoptosis triggering molecules.

Sadly I'm now in remote place right now, where I can't reach my notes and stuff. But as soon as I reach my notes, I will write more detailed pathway.

Sincerely

"when a telomere becomes dysfunctional due to telomere shortening or removal of telomere proteins, a full DNA damage checkpoint is activated via ATM or ATR protein kinases, members of the PI-3 protein kinase-like family. Activation of the checkpoint leads to accumulation of γH2AX and other DNA repair proteins" (Jacob & Price in 2007 in the journal of "Molecular and Cellular Biology")

by the way, it is not G1/S transition checkpoint, but intra-S-phase checkpoint (ATM- and/or ATR-mediated DNA damage checkpoint), that is, right after G1/S transition. This is crucial, since when a cell passes G1/S transition, it has to divide anyways, because it is the most important decision making step. Getting stuck in intra-S-phase checkpoint makes step pause the cell cycle, and try to solve problem.

Also, abscence of telomere regions makes chromosomal endings "sticky". This is consequence of removal of telomeric repeats. As you recall, telomere repeats are important for capping the ending of the chromosome. And telomere shortening happens because of the abscence of 3'OH group of leading strand to fill in the missing nucleotides to replace RNA primer. Now, if telomerase is dysfunctional, these ends would not be able to cap, and since there are 46 chromosomes in humans, then there are 46 pairs of one strand of telomere repeat. Since these repeats are not capped, they can bind to each other and form complexes. Those sticky complexes are the main problem at intra-S-phase checkpoint. They are impossible to divide into two, and thus they may cause aneuploidy if intra-S-phase checkpoint would not work.

Mechanism of how telomere works you can see in this paper:

http://www.nature.com/nature/journal/v467/n7312/full/nature09353.html

"Failure to maintain proper telomere length or structure can result in chromosome rearrangements, cell apoptosis, senescence, or permanent inhibition of cell proliferation. Failure to properly maintain telomere ends can result in uncapped telomeres that activate PIKK such as the ATM protein" (http://www.nature.com/jid/journal/v124/n4/full/5602773a.html)

And all the papers point on "p53-dependent apoptotic response" in abscence of telomeres. That is, I couldn't find a direct indormation on the mechanism of apoptosis in p53-independent pathway.

Many thanks Elbay! His help was of great service to my work.