ALTernative Telomere Maintenance in Stem Cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05795
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
Telomeres are the ends of our linear chromosomes and protect the genetic material against enzymatic attack. They are essential for long-term survival of cells and prevent genome instability. Telomeres shorten with each cell division, and when they become critically short they cause a cessation of cell growth, or cell death. This limits the number of times cells can divide and therefore represents a powerful tumor suppressive mechanism. Stem cells however, possess unlimited proliferation potential, which can only be achieved by counteracting replication-associated telomere loss. They do so by activating telomerase, which is an enzyme that specifically elongates telomeres. Similarly, cancer cells activate telomerase to gain immortality, pointing out a parallel between stem cells and cancer cells. Telomerase activation has other side effects besides providing immortality, which are deregulation of the packaging dynamics of the genetic material, as well as altering gene expression, both of which represent undesired side effects that could interfere with the use of stem cells for therapy. We have discovered the mechanism for an alternative pathway for telomere lengthening, called ALT. This proposal is designed to investigate the effects of ALT on stem cell generation, long-term culture, genome stability and differentiation. The goal of this proposal is to develop an alternative method to maintain telomeres, potentially eliminating telomerase expression-associated side effects.
Statement of Benefit to California: 
The use of stem cells for therapy is critically dependent on the capabilities to prevent the cells from transformation and the accumulation of other deleterious alterations during their handling and growth. Telomeres are the natural ends of linear chromosomes. They shorten with each cell division, until they cause a cessation of cell growth, or cell death. This limits the number of times cells can divide and represents a powerful tumor suppressive mechanism. Telomere shortening also limits the efficiency of reprogramming of aged cells and cells from older individuals. Telomerase is an enzyme that lengthens telomeres, and is activated during the reprogramming of cells, but also in cancer cells and renders them immortal. Telomerase activation has other side effects besides providing immortality, which are deregulation of the packaging dynamics of the genetic material, as well as altering gene expression, both of which represent undesired side effects that could interfere with the use of stem cells for therapy. We discovered the mechanism for an alternative pathway to telomerase for telomere length maintenance (ALT), and this proposal is designed to investigate the effects of ALT on stem cell generation, long-term culture, genome stability and differentiation. This project will benefit California and its citizens by providing the means for telomere lengthening in aged cells, stem cells and reprogrammed cells, while avoiding the deleterious side effects of telomerase.

© 2013 California Institute for Regenerative Medicine