Multiple Mechanisms Contribute To Telomere Maintenance.

Abstract

The unlimited growth potential of tumors depends on telomere maintenance and typically depends on telomerase, an RNA-dependent DNA polymerase, which reverse transcribes the telomerase RNA template, synthesizing telomere repeats at the ends of chromosomes. Studies in various model organisms genetically deleted for telomerase indicate that several recombination-based mechanisms also contribute to telomere maintenance. Understanding the molecular basis of these mechanisms is critical since some human tumors form without telomerase, yet the sequence is maintained at the telomeres. Recombination-based mechanisms also likely contribute at some frequency to telomere maintenance in tumors expressing telomerase. Preventing telomere maintenance is predicted to impact tumor growth, yet inhibiting telomerase may select for the recombination-based mechanisms. Telomere recombination mechanisms likely involve altered or unregulated pathways of DNA repair. The use of some DNA damaging agents may encourage the use of these unregulated pathways of DNA repair to be utilized and may allow some tumors to generate resistance to these agents depending on which repair pathways are altered in the tumors. This review will discuss the various telomere recombination mechanisms and will provide rationale regarding the possibility that L1 retrotransposition may contribute to telomere maintenance in tumors lacking telomerase.