Dear Walt, Tom, Josh, David, Harold, and others participating in the telomere discussion.
When I read through your comments on telomeres, I did not see much mentioned about the molecular biology
of telomeres that has been discovered in the past 5-10 years.
Here is a short summary of the 15 major molecular mechanisms that affect/regulate telomere length
which have not been discussed much on LA-GRG. (I purposely left off telomerase and hTERC,
which has been discussed at length).
I did not order them in order of importance (all of these discoveries are important).
Instead, I hope each of these major molecular mechanisms controlling telomere length will inspire each
of you to learn more and share with us what you learned. (please share what you learned with me).
I think we must “move on” from a simple discussion of “telomerase activation” to that of a much larger view
of what controls telomeres, which includes long non-coding RNA (TERRA), histone trimethylation (H3K9 and H4K20),
COMPASS (H3K4me3), histone H3K79 trimethylation, histone hyperacetylation, Rb proteins, subtelomeric DNA
methylation (DNMTs), the miR-290 family, Shelterin proteins, Rap-1, SIRT1, Tankyrases, SIRT6, and the ALT
mechanism are all very important aspects of telomere length control.
It is NOT all due to the enzyme telomerease or the p53-mediated DNA-damage response (DDR).
Here are the “top 15” things that I have not seen LA-GRG members discussing much about:
1. Both ends of the chromosome arm are important for lifespan!
Each chromosome arm as two ends – the pericentromeric area and the telomeric area. Both must be silenced
by the formation of heterochromatin. Pericentromeric heterochromatin (pericentromere DNA) and the telomeric
heterochromatin are both equally important in lifespan! Disruptions in histone protein modifications and with DNA
methylation in the pericentromeric region result in chromosomal instability, recombination, and aneuploidy. In old
age, as many as 80% of cells display features of aneuploidy in organs like the liver. Disruptions in histone protein
modifications and with DNA methylation of the subtelomeric regions likewise regulated telomere length and the ALT
pathway. I noted that LA-GRG discussions on telomere length rarely mentions pericentromeric DNA stability. Instability
in this area is a major factor in the development of aneuploidy, cancer, and aging. Let’s include in the discussion of the
“end of the chromosome arm” more information about the “beginning of the chromosome arm”.
Here is an illustration that compares the silencing mechanism of the “end of the chromosome arm” and the “pericentromeric DNA”
Ref for illustration: http://ift.tt/1EO9diB